Vanilloid receptor ligands and their use in treatments

ABSTRACT

Compounds having the general structure  
                 
and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

The present invention is a divisional and claims the benefit of U.S.application Ser. No. 10/316,295 filed on Dec. 10, 2002, U.S. ProvisionalApplication Nos. 60/339,161 filed Dec. 10, 2001, 60/344,737, filed Dec.21, 2001, 60/383,331, filed May 22, 2002 and 60/402,422, filed Aug. 8,2002, which are hereby incorporated by reference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al.,2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al.,2000). VR1 is highly expressed in primary sensory neurons (Caterina etal., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey et al.,2000, Helliwell et al., 1998, Cortright et al., 2001). These sensoryneurons innervate many visceral organs including the dermis, bones,bladder, gastrointestinal tract and lungs; VR1 is also expressed inother neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-Cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). Theresults of acute activation by capsaicin in humans was pain at injectionsite and in other species increased behavioral sensitivity to sensorystimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skinin humans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,Singh et al., 2001). This evidence indicates that capsaicin through it'sactivation of VR1 can regulate afferent and efferent function of sensorynerves. Sensory nerve involvement in diseases could therefore bemodified by molecules which effect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to have reduced sensorysensitivity to thermal and acid stimuli (Caterina et al., 2000)). Thissupports the concept that VR1 contributes not only to generation of painresponses (i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

VR1 agonists or antagonists have use as analgesics for the treatment ofpain of various genesis or aetiology, for example acute, inflammatoryand neuropathic pain, dental pain and headache, particularly vascularheadache such as migraine, cluster headache and mixed vascular syndromesas well as non-vascular, tension headache. They are also useful asanti-inflammatory agents for the treatment of inflammatory diseases orconditions, for example the treatment of arthritis and rheumaticdiseases, osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders (e.g. uvetis), inflammatory or unstable bladder disorders(e.g. cystitis and urinary incontinence), psoriasis and skin complaintswith inflammatory components, as well as other chronic inflammatoryconditions. They are, in particular, useful in the treatment ofinflammatory pain and associated hyperalgesia and allodynia. They arealso useful in the treatment of neuropathic pain and associatedhyperalgesia and allodynia, e.g. trigeminal or herpetic neuralgia,diabetic neuropathy pain, causalgia, sympathetically maintained pain anddeafferentation syndromes such as brachial plexus avulsion. They arealso indicated for the use in the prophylactic or curative treatment ofasthma, of epithelial tissue damage or dysfunction, e.g. spontaneouslesions, of herpes simplex, and in the control of disturbances ofvisceral motility at respiratory, genitourinary, gastrointestinal orvascular e.g. for treating wounds, burns, allergic skin reactions,pruritis and vitiligo, for the prophylactic or curative treatment ofgastrointestinal disorders such as gastric ulceration, duodenal ulcers,inflammatory bowel disease and diarrhea, gastric lesions induced bynecrotising agents, for example ethanol or chemotherapeutic agents, hairgrowth, for the treatment of vasomotor or allergic rhinitis and for thetreatment of bronchial disorders or bladder disorders, such as bladderhyper-reflexia.

BIBLIOGRAPHY

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SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders. Analogously, the inventionalso comprises pharmaceutical compositions comprising the compounds,methods for the treatment of vanilloid-receptor-mediated diseases, suchas inflammatory or neuropathic pain, asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis diseases, using the compounds and compositions ofthe invention, and intermediates and processes useful for thepreparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure

or a pharmaceutically acceptable salt thereof, wherein A, R¹, R², R³,R⁴, X and Y are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

One aspect of the current invention relates to compounds having thegeneral structure:

wherein:

R¹ is

or a naphthyl or saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and thenaphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or3 substituents independently selected from R⁵, R⁶ and R⁷;

R² is H, hydroxy, halo, C₁₋₆alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷; or R¹ and R² together are

R³ is H or C₁₋₄alkyl; or R¹ and R³ together are

R⁴ is

R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is optionallyvicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the carbon atoms of the heterocycleand bridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl; or R⁴is 10-membered bicyclic ring comprising fused 6-membered rings,containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbonatoms, with at least one of the 6-membered rings being aromatic, whereinthe carbon atoms are substituted by H, halo, OR^(a), NR^(a)R^(a),C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbon atoms may beadditionally substituted by ═O; except that when R¹ is 4-Chlorophenyl,3-bromophenyl, 3-nitrophenyl, 2-nitro-3-Chlorophenyl,3,4-methylenedioxyphenyl, 3-methylthiophenyl or 2,3,4-methoxyphenyl,then R⁴ is not phenyl substituted by 1 or 2 substituents selected fromhalo and C₁₋₄alkyl; and R¹ and R⁴ are not both 3,4-methylenedioxyphenyl;and when R¹ is 4-trifluoromethylphenyl, then R⁴ is not pyridinyl,2-methyl-4-aminoquinolinyl or 3,3-dimethyl-1,3-dihydroindol-2-on-6-yl;

R⁵ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)C₁₋₆alkylOR^(a); or R⁵ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S;

R⁶ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)C₁₋₆alkylNR^(a)R^(a) or—NR^(a)C₁₋₆alkylOR^(a); or R⁵ and R⁶ together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the bridge are substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₆alkyl, (═O), —OC₁₋₆alkyl, —NR^(a)C₁₋₆alkyl,—C₁₋₆alkylOR^(a) and C₁₋₆alkylNR^(a)R^(a), and the available N atoms ofthe bridge are substituted by R^(a), —C₁₋₆alkylOR^(a) orC₁₋₆alkylNR^(a)R^(a);

R⁷ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a);

R⁸ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)C₁₋₆alkylNR^(a)R^(a) or—NR^(a)C₁₋₆alkylOR^(a); or R⁷ and R⁸ together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the bridge are substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₆alkyl, (═O), —O—C₁₋₆alkyl, —NR^(a)C₁₋₆alkyl,—C₁₋₆alkylOR^(a) and C₁₋₆alkylNR^(a)R^(a), and the available N atoms ofthe bridge are substituted by R^(a), —C₁₋₆alkylOR^(a) orC₁₋₆alkylNR^(a)R^(a);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, 'OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a);

R¹⁰ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹¹ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylR^(c),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; or R¹⁰and R¹¹ together are a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the each of the carbon atoms in thebridge is substituted by H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl,—NR^(a)R^(a), —C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); wherein if R¹⁰, R¹², R¹³ and R¹⁴ are all H, then R¹¹is not —O—C₁₋₆alkylNR^(a)R^(a) or —O—C₁₋₆alkylOR^(a);

R¹² is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; or R¹¹ and R¹² together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the each ofthe carbon atoms in the bridge is substituted by H, ═O, —OR^(a),—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a), —C₁₋₆alkylNR^(a)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl, —NR^(a)C(═O)C₁₋₆alkyl,—C₁₋₃alkylOC(═O)C₁₋₆alkyl or —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(a),—C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c);

when R¹ is 4-C₁₋₆alkylphenyl or 2,4-dimethylphenyl, then R¹¹ isC₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylR^(c), —O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; or R¹⁰and R¹¹ together are -L³-NR^(a)—, respectively, or -L⁴-O—, respectively;or R¹¹ and R¹² are —NR^(a)-L³-, -L³—NR^(a)—, —O-L⁴- or -L⁴-O—; or R¹² is—NR^(a)R^(b); or R⁴ is 10-membered bicyclic ring comprising fused6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainderbeing carbon atoms, with at least one of the 6-membered rings beingaromatic, wherein the carbon atoms are substituted by H, halo, OR^(a),NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbon atoms maybe additionally substituted by ═O; or R⁴ is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selectedfrom O, N and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the heterocycle and bridge are substituted by 1, 2 or 3substituents independently selected from C₂₋₉alkyl, C₁₋₄haloalkyl, halo,nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl;

R¹³ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹⁴ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R^(a) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl;

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a);

R^(c) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(c) is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the carbon atoms of the heterocycle aresubstituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fusedphenyl ring is substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a);

L¹ is a bond, —CH₂CH₂— or —CH═CH—;

L² is NR^(a), O, S(═O)_(n), —N═CH—, —CH₂NR^(a)—, —CH═N— or —NR^(a)CH₂—;

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

L⁴ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0 or 1 atoms independently selected from O, N andS, wherein at least one of the carbon atoms in the bridge is substitutedby ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OC₁₋₆alkyl, —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)C₁₋₆alkyl, —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

X is O, S or NR^(a); or X and R² together are ═N—CH═CH—, ═C—O—, ═C—S—,or ═C—NR^(a)—;

Y is NH or O; and

n is independently, at each instance, 0, 1 or 2; with the proviso thatwhen R¹ is 4-chlorophenyl, then R⁴ is not 3-methoxyphenyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

or a naphthyl or saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and thenaphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or3 substituents independently selected from R⁵, R⁶ and R⁷;

R² is H, hydroxy, halo, C₁₋₆alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷; and

R³ is H or C₁₋₄alkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is independently, at each instance,C₂₋₉alkyl or C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶ and R⁷.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶ and R⁷.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶ and R⁷.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ and R² together are

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ and R³ together are

In another embodiment, in conjunction with the novel compoundembodiments above and below, X and R together are ═N—CH═CH—, ═C—O—,═C—S—, or ═C—NR^(a)—.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a); and

Y² is —NR^(a)— or —O—.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0 or 1 atoms independently selected from O, N andS, wherein the each of the carbon atoms in the bridge is substituted byH, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a); and

Y² is —NR^(b)— or —O—.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a); and

Y² is —NR^(b)— or —O—.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a) —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a); and

Y² is —NR^(b)— or —O—.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆—O—R^(a); and

Y² is —NR^(a)— or —O—.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is 10-membered bicyclic ring comprisingfused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with theremainder being carbon atoms, with at least one of the 6-membered ringsbeing aromatic, wherein the carbon atoms are substituted by H, halo,OR^(a), NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbonatoms may be additionally substituted by ═O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

R¹⁰ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹¹ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylR^(c),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl;C₁₋₆alkylNR^(a)R^(a);

R¹² is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹³ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; and

R¹⁴ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; wherein one of R¹⁰ and R¹² is not H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents selected from halo,C₁₋₄haloalkyl, —OR^(a) and —NR^(a)R^(a).

Another aspect of the invention relates to a compound having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

n is independently, at each instance, 0, 1 or 2.

R¹ is

or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵; or R¹ is R^(e) substituted by 1, 2 or 3substituents independently selected from R⁵;

R¹⁵ is, independently, in each instance, R¹⁰, C₁₋₈alkyl substituted by0, 1 or 2 substituents selected from R¹⁰, —(CH₂)_(n)phenyl substitutedby 0, 1, 2 or 3 substituents independently selected from R¹⁰, or asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the heterocycle or fused phenylring is substituted by 0, 1, 2 or 3 substituents independently selectedfrom R¹⁰;

R¹⁶ is, independently, in each instance, H, halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl or C₁₋₃alkyl;

R⁴ is

R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is optionallyvicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the carbon atoms of the heterocycleand bridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, oxo,—OR^(d), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —OC₁₋₆alkylC(═O)OR^(d), —NR^(d)R^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(d)C₁₋₆alkyl and —NR^(d)C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d),—C₁₋₆alkyl, —C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f); or R⁴ is10-membered bicyclic ring comprising fused 6-membered rings, containing0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with atleast one of the 6-membered rings being aromatic, wherein the carbonatoms are substituted by H, halo, OR^(d), NR^(d)R^(d), C₁₋₆alkyl andC₁₋₃haloalkyl; and saturated carbon atoms may be additionallysubstituted by ═O; but in no instance is R⁴ 3,5-ditrifluoromethylphenylor 3-trifluoromethyl-4-fluorophenyl;

R⁵ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d), —NR^(d)R^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), naphthyl, —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(d)R^(d), —NR^(d)C(═O)R^(d), —NR^(d)C(═O)NR^(d)R^(d),—NR^(d)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(d)R^(d), —NR^(d)S(═O)₂(C₁₋₆alkyl),—OC(═O)NR^(d)R^(d), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁵ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S, substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰;

R⁶ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl,—NR^(d)C₂₋₆alkylNR^(d)R^(d) or NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d),—C₁₋₆alkylNR^(d)R^(d), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁰; or R⁶ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁷ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl,—NR^(d)C₂₋₆alkylNR^(d)R^(d), —NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d),—C₁₋₆alkylNR^(d)R^(d) or —S(C₁₋₆alkyl); or R⁷ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R⁸ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl,—NR^(d)C₂₋₆alkylNR^(d)R^(d) or —NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d),—C₁₋₆alkylNR^(d)R^(d), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁰, or R⁸ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁹ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)R^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d) or—NR^(d)C₂₋₆alkylOR^(d), —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(d)R^(d), —NR^(d)C(═O)(C₁₋₆alkyl), —NR^(d)C(═O)NR^(d)R^(d),—NR^(d)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(d)R^(d), —NR^(d)S(═O)₂(C₁₋₆alkyl),—OC(═O)NR^(d)R^(d), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁹ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁹ is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom,wherein the ring is substituted with 0, 1 or 2 substituentsindependently selected from halo, C₁₋₂haloalkyl and C₁₋₃alkyl; whereinat least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d) or—S(C₁₋₆alkyl);

R¹⁰ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d);

R¹¹ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹¹ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹¹ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ and R¹¹together are a saturated or unsaturated 3- or 4-atom bridge containing0, 1, 2 or 3 atoms selected from O, N and S with the remaining atomsbeing carbon, so long as the combination of O and S atoms is not greaterthan 2, wherein the each of the carbon atoms in the bridge issubstituted by H, ═O, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d),—C(═NR^(d))NR^(d)R^(d), —OR^(d), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d), and any nitrogenatoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d), —C₁₋₆alkyl,—C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f);

R¹² is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹² is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); wherein if R¹¹or R¹³ is CF₃, then R¹² is not F; or R¹¹ and R¹² together are asaturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3atoms selected from O, N and S with the remaining atoms being carbon, solong as the combination of O and S atoms is not greater than 2, whereinthe each of the carbon atoms in the bridge is substituted by H, ═O,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d), and any nitrogenatoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d), —C₁₋₆alkyl,—C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f);

R¹³ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹³ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹³ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d);

R¹⁴ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁴ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁴ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d);

R^(d) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl;

R^(e) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl,1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl,pyrazol-3-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine,1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine,1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine, 2H-5,6-dihydropyran,2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline,2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydroisothiazole,2,5-dihydroisoxazole, 2,5-dihydroisothiazole, 2,3-dihydroisoxazole,4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole,4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole,1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4]thidiazole, 2,5-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2]thiazine,3,6-dihydro-2H-[1,2]thiazine, 3,4-dihydro-2H-[1,2]thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dithiazine,2,3-dihydro-[1,4,2]dioxazine, 3,4-dihydro-2H-[1,3,4]oxadiazine,3,6-dihydro-2H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,3,5]oxadiazine,3,6-dihydro-2H-[1,3,5]oxadiazine, 5,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,2,5]oxadiazine, 3,4-dihydro-2H-[1,3,4]thiadiazine,3,6-dihydro-2H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,3,5]thiadiazine,3,6-dihydro-2H-[1,3,5]thiadiazine, 5,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,2,5]thiadiazine, 5,6-dihydro-2H-[1,2,3]oxadiazine,3,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-2H-[1,2,3]thiadiazine,3,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-[1,4,3]oxathiazine,5,6-dihydro-[1,4,2]oxathiazine, 2,3-dihydro-[1,4,3]oxathiazine,2,3-dihydro-[1,4,2]oxathiazine, 4,5-dihydropyridine,1,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin,3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine,4,5-dihydropyridazine, 1,2-dihydropyridazine, 2,3-dihydropyrirnidine,2,5-dihydropyrirnidine, 5,6-dihydropyrirnidine, 3,6-dihydropyrirnidine,4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine and 1,4,2-oxathiazine, whereinthe heterocycle is optionally vicinally fused with a saturated orunsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S;

R^(f) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(d) and —NR^(d)R^(d); or R^(f) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(d) and—NR^(d)R^(d); and

R^(g) is hydrogen or —CH₃.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁶ is halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl or C₁₋₃alkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁰ is independently, at each instance,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₅alkyl, halo or C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is naphthyl substituted by 0, 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is R^(e) substituted by 0, 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is R^(e) substituted by 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁰ and R¹¹ together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the each ofthe carbon atoms in the bridge is substituted by H, ═O, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d), and any nitrogenatoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d), —C₁₋₆alkyl,—C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f); or

R¹¹ and R¹² together are a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the each of the carbon atoms in thebridge is substituted by H, ═O, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d),—C(═NR^(d))NR^(d)R^(d), —OR^(d), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d), and any nitrogenatoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d), —C₁₋₆alkyl,—C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₉alkyl, C₁₋₄haloalkyl, halo,nitro, cyano, oxo, —OR^(d), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d), —OC₁₋₆alkylC(═O)OR^(d),—NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(d)C₁₋₆alkyl and —NR C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d),—C₁₋₆alkyl, —C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the heterocycle and bridge are substituted by 1, 2 or 3substituents independently selected from C₁₋₉alkyl, C₁₋₄haloalkyl, halo,nitro, cyano, oxo, —OR^(d), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d), —OC₁₋₆alkylC(═O)OR^(d),—NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(d)C₁₋₆alkyl and —NR^(d)C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(d),—C₁₋₆alkyl, —C₁₋₆alkylNR^(d)R^(d), —C₁₋₃alkylC(═O)OR^(d),—C₁₋₃alkylC(═O)NR^(d)R^(d), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(d)C(═O)C₁₋₆alkyl, —C(═O)R^(f) or —C₁₋₃alkylR^(f).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is 10-membered bicyclic ring comprisingfused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with theremainder being carbon atoms, with at least one of the 6-membered ringsbeing aromatic, wherein the carbon atoms are substituted by H, halo,OR^(d), NR^(d)R^(d), C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbonatoms may be additionally substituted by ═O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is 10-membered bicyclic ring comprisingfused 6-membered rings, containing 1, 2, 3 or 4 N atoms with theremainder being carbon atoms, with at least one of the 6-membered ringsbeing aromatic, wherein the carbon atoms are substituted by H, halo,OR^(d), NR^(d)R^(d), C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbonatoms may be additionally substituted by ═O.

Another aspect of the invention relates to a compound having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

Y is NH, O or S;

R¹ is

or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵; or R¹ is R^(e) substituted by 1, 2 or 3substituents independently selected from R⁵;

R¹⁵ is, independently, in each instance, R¹⁰, C₁₋₈alkyl substituted by0, 1 or 2 substituents selected from R¹⁰, —(CH₂)_(n)phenyl substitutedby 0, 1, 2 or 3 substituents independently selected from R¹⁰, or asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the heterocycle or fused phenylring is substituted by 0, 1, 2 or 3 substituents independently selectedfrom R¹⁰;

R¹⁶ is, independently, in each instance, H, halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl or C₁₋₃alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R⁵,—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s); and the ring andbridge carbon atoms are substituted with 0, 1 or 2 ═O groups; but in noinstance is R⁴ 3,5-ditrifluoromethylphenyl or3-trifluoromethyl-4-fluorophenyl;

R⁵ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d), —NR^(d)R^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), naphthyl, —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(d)R^(d), —NR^(d)C(═O)R^(d), —NR^(d)C(═O)NR^(d)R^(d),—NR^(d)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(d)R^(d), —NR^(d)S(═O)₂(C₁₋₆alkyl),—OC(═O)NR^(d)R^(d), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁵ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S, substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰;

R⁶ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl,—NR^(d)C₂₋₆alkylNR^(d)R^(d) or —NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d),—C₁₋₆alkylNR^(d)R^(d), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁰; or R⁶ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁷ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl,—NR^(d)C₂₋₆alkylNR^(d)R^(d), —NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d),—C₁₋₆alkylNR^(d)R^(d) or —S(C₁₋₆alkyl); or R⁷ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R⁸ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl,—NR^(d)C₂₋₆alkylNR^(d)R^(d), —NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d),—C₁₋₆alkylNR^(d)R^(d), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁰, or R⁶ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁹ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d), NR^(d)R^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d) or—NR^(d)C₂₋₆alkylOR^(d), —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(d)R^(d), —NR^(d)C(═O)(C₁₋₆alkyl), —NR^(d)C(═O)NR^(d)R^(d),—NR^(d)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(d)R^(d), —NR^(d)S(═O)₂(C₁₋₆alkyl),—OC(═O)NR^(d)R^(d) or a —(CR^(q)R^(q))_(o)phenyl wherein the phenyl issubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰; or R⁹ is —(CR^(q)R^(q))_(o)Het wherein Het is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁹ is a saturated or unsaturated 4-or 5-membered ring heterocycle containing a single nitrogen atom,wherein the ring is substituted with 0, 1 or 2 substituentsindependently selected from halo, C₁₋₂haloalkyl and C₁₋₃alkyl; whereinat least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d),—NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d),—NR^(d)C₂₋₆alkylOR^(d), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d) or—S(C₁₋₆alkyl);

R¹⁰ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR or R¹⁰ is C₁₋₄alkylsubstituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d),—C(═NR^(d))NR^(d)R^(d), —OR^(d), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d);

R^(d) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl;

R^(e) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl,1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl,pyrazol-3-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine,1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine,1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine, 2H-5,6-dihydropyran,2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline,2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydroisothiazole,2,5-dihydroisoxazole, 2,5-dihydroisothiazole, 2,3-dihydroisoxazole,4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole,4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole,1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4]thidiazole, 2,5-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2]thiazine,3,6-dihydro-2H-[1,2]thiazine, 3,4-dihydro-2H-[1,2]thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dithiazine,2,3-dihydro-[1,4,2]dioxazine, 3,4-dihydro-2H-[1,3,4]oxadiazine,3,6-dihydro-2H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,3,5]oxadiazine,3,6-dihydro-2H-[1,3,5]oxadiazine, 5,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,2,5]oxadiazine, 3,4-dihydro-2H-[1,3,4]thiadiazine,3,6-dihydro-2H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,3,5]thiadiazine,3,6-dihydro-2H-[1,3,5]thiadiazine, 5,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,2,5]thiadiazine, 5,6-dihydro-2H-[1,2,3]oxadiazine,3,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-2H-[1,2,3]thiadiazine,3,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-[1,4,3]oxathiazine,5,6-dihydro-[1,4,2]oxathiazine, 2,3-dihydro-[1,4,3]oxathiazine,2,3-dihydro-[1,4,2]oxathiazine, 4,5-dihydropyridine,1,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin,3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine,4,5-dihydropyridazine, 1,2-dihydropyridazine, 2,3-dihydropyrimidine,2,5-dihydropyrimidine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine,4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine and 1,4,2-oxathiazine, whereinthe heterocycle is optionally vicinally fused with a saturated orunsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S;

R^(f) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(d) and —NR^(d)R^(d); or R^(f) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(d) and—NR^(d)R^(d);

R^(g) is hydrogen or —CH₃;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR ,—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q).

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is S.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₅alkyl, halo or C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is a naphthyl substituted by 0, 1, 2 or3 substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is R^(e) substituted by 1, 2 or 3substituents independently selected from R⁵;

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁵ is —(CH₂)_(n)phenyl substituted by 0,1, 2 or 3 substituents independently selected from R¹⁰.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁵ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR¹⁰.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁵ is C₁₋₈alkyl substituted by 0, 1 or 2substituents selected from R¹⁰.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁵ is selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(50 O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R )C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl), -13N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(d)R^(d), —C(═NR^(d))NR^(d)R^(d), —OR^(d),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(d)R^(d),—OC(═O)N(R^(d))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(d)R^(d),—OC₂₋₆alkylOR^(d), —SR^(d), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(d)R^(d), —S(═O)₂N(R^(d))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(d))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(d))C(═O)NR^(d)R^(d),—NR^(d)R^(d), —N(R^(d))C(═O)(C₁₋₈alkyl), —N(R^(d))C(═O)O(C₁₋₈alkyl),—N(R^(d))C(═O)NR^(d)R^(d), —N(R^(d))C(═NR^(d))NR^(d)R^(d),—N(R^(d))S(═O)₂(C₁₋₈alkyl), —N(R^(d))S(═O)₂NR^(d)R^(d),—NR^(d)C₂₋₆alkylNR^(d)R^(d) and —NR^(d)C₂₋₆alkylOR^(d).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁶ is, independently, in each instance,halo, —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl or C₁₋₃alkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is an unsaturated 6-membered ringcontaining 0 atoms selected from O, N and S that is vicinally fused witha saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3atoms selected from O, N and S with the remaining atoms being carbon, solong as the combination of O and S atoms is not greater than 2, whereinthe ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(m), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR,—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR²; and the ring andbridge carbon atoms are substituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 1, 2 or 3 atoms selected from O, N and S thatis vicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0 atoms selected from O, N and S with the remaining atomsbeing carbon, so long as the combination of O and S atoms is not greaterthan 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s); and the ring andbridge carbon atoms are substituted with 0, 1 or 2 ═O groups; but in noinstance is R⁴ 3,5-ditrifluoromethylphenyl or3-trifluoromethyl-4-fluorophenyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 6-memberedring containing 0 atoms selected from O, N and S that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein thering and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s, —N(R)^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂ ₆alkylNR^(m)R²,—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s); and the ring andbridge carbon atoms are substituted with 0, 1 or 2 ═O groups; but in noinstance is R⁴ 3,5-ditrifluoromethylphenyl or3-trifluoromethyl-4-fluorophenyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 1, 2 or 3 atoms selected from O, N and S thatis vicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 1, 2 or 3 atoms selected from O, N and S with the remainingatoms being carbon, so long as the combination of O and S atoms is notgreater than 2, wherein the ring and bridge are substituted by 0, 1, 2or 3 substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s); and the ring andbridge carbon atoms are substituted with 0, 1 or 2 ═O groups; but in noinstance is R⁴ 3,5-ditrifluoromethylphenyl or3-trifluoromethyl-4-fluorophenyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is independently, at each instance,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(d)R^(d), —OC₂₋₆alkylOR^(d),—NR^(d)R^(d), —NR^(d)C₁₋₄haloalkyl, —NR^(d)C₂₋₆alkylNR^(d)R^(d) or—NR^(d)C₂₋₆alkylOR^(d), —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(d)R^(d), —NR^(d)C(═O)(C₁₋₆alkyl), —NR^(d)C(═O)NR^(d)R^(d),—NR^(d)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(d), —C₁₋₆alkylNR^(d)R^(d),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(d)R^(d), —NR^(d)S(═O)₂(C₁₋₆alkyl) or—OC(═O)NR^(d)R^(d).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is a —(CR^(q)R^(q))_(o)phenyl whereinthe phenyl is substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is —(CR^(q)R^(q))_(o)Het wherein Het isa saturated or unsaturated 5- or 6-membered ring heterocycle containing1, 2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁹ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl.

Another aspect of the invention relates to a compound having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

Y is O or S;

n is independently, at each instance, 0, 1 or 2.

R¹ is

or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵; or R¹ is R^(i) substituted by 1, 2 or 3substituents independently selected from R⁵;

R¹⁵ is, independently, in each instance, R¹⁰, C₁₋₈alkyl substituted by0, 1 or 2 substituents selected from R¹⁰, —(CH₂)_(n)phenyl substitutedby 0, 1, 2 or 3 substituents independently selected from R¹⁰, or asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S that isoptionally vicinally fused with a saturated or unsaturated 3- or 4-atombridge containing 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, the heterocycle and bridge beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromR¹⁰;

R¹⁶ is, independently, in each instance, H, halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, —OC₁₋₃alkyl, —C₁₋₂haloalkyl, —OC₁₋₂haloalkyl orC₁₋₃alkyl;

R⁴ is

wherein when R¹ is bromophenyl, methylphenyl or trifluoromethylphenyl,R⁴ is not trifluoromethylphenyl or trifluoromethylhalophenyl; or R⁴ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 2, wherein each of the carbon atoms ofthe heterocycle is substituted by H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo,cyano, oxo, —OR^(h), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h), —OC₁₋₆alkylC(═O)OR^(h),—NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl, —NR^(h)C₂₋₆alkylNR^(h)R^(h),—NR^(h)C₂₋₆alkylOR^(h), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(h)C₁₋₆alkyl or —NR^(h)C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and eachof the available nitrogen atoms in the heterocycle are substituted by H,—C₁₋₆alkylOR^(h), —C₁₋₆alkyl, —C₁₋₆alkylNR^(h)R^(h),—C₁₋₃alkylC(═O)OR^(h), —C₁₋₃alkylC(═O)NR^(h)R^(h),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(h)C(═O)C₁₋₆alkyl, —C(═O)R^(j)or —C₁₋₃alkylR^(j); or R⁴ is an 8-, 9-, 10- or 11-membered bicyclicring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selectedfrom S and O with the remainder being carbon atoms, wherein each of thecarbon atoms of the ring is substituted by H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, cyano, oxo, —OR^(h), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h), —OC₁₋₆alkylC(═O)OR^(h),—NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl, —NR^(h)C₂₋₆alkylNR^(h)R^(h),—NR^(h)C₂₋₆alkylOR^(h), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(h)C₁₋₆alkyl or —NR^(h)C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the ring are substituted by H,—C₁₋₆alkylOR^(h), —C₁₋₆alkyl, —C₁₋₆alkylNR^(h)R^(h),—C₁₋₃alkylC(═O)OR^(h), —C₁₋₃alkylC(═O)NR^(h)R^(h),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(h)C(═O)C₁₋₆alkyl, —C(═O)R^(j)or —C₁₋₃alkylR^(j);

R⁵ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), naphthyl,—CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl), —C(═O)NR^(h)R^(h),—NR^(h)C(═O)R^(h), —NR^(h)C(═O)NR^(h)R^(h), —NR^(h)CO₂(C₁₋₆alkyl),—C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(h)R^(h), —S(═O)_(n)(C₁₋₆alkyl),—S(═O)₂NR^(h)R^(h), —NR^(h)S(═O)₂(C₁₋₆alkyl), —OC(═O)NR^(h)R^(h), aphenyl ring substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰; or R⁵ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and S,substituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰;

R⁶ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h) or —NR^(h)C₂₋₆alkylOR^(h), —C₁₋₈alkylOR^(h),—C₁₋₆alkylNR^(h)R^(h), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁰; or R⁶ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁷ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,bromo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), —C₁₋₈alkylOR^(h),—C₁₋₆alkylNR^(h)R^(h) or —S(C₁₋₆alkyl); or R⁷ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R⁸ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), —C₁₋₈alkylOR^(h),—C₁₋₆alkylNR^(h)R^(h), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁰, or R⁸ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁹ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl, —NR^(h)R^(h) or—NR^(h)C₂₋₆alkylOR^(h), —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(h)R^(h), —NR^(h)C(═O)(C₁₋₆alkyl), —NR^(h)C(═O)NR^(h)R^(h),—NR^(h)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(h)R^(h),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(h)R^(h), —NR^(h)S(═O)₂(C₁₋₆alkyl),—OC(═O)NR^(h)R^(h), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁹ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰; wherein at least one of R⁵, R⁶, R⁷, R⁸and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), —C₁₋₈alkylOR^(h),—C₁₋₆alkylNR^(h)R^(h) or —S(C₁₋₆alkyl); or R⁹ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R¹⁰ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1 or 2 atoms selectedfrom N, O and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)NR^(h)R^(h),—C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h);

R¹¹ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹¹ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹¹ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h);

R¹² is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(h)R^(h), —OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹² is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆,alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h)and —NR^(h)C₂₋₆alkylOR^(h); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h);

R¹³ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹³ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —OC(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹³ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h);

R¹⁴ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹⁴ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1 or 2 atoms selectedfrom N, O and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹⁴ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)NR^(h)R^(h),—C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h);

R^(h) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,—OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl;

R^(i) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazol-5-yl, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-3-yl,imidazol-4-yl, 1,2,4-triazole, 1,2,4-triazole, isoxazole, pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine,1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine,1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine, 2H-5,6-dihydropyran,2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazolin-1-yl, 2-imidazolin-2-yl, 2-imidazolin-5-yl, 3-imidazoline,2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole,4,5-dihydroisoxazole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole,2,5-dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole,2,3-dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole,2,3-dihydrothiazole, 2,5-dihydrothiazole, 1,3,4-oxathiazolidine,1,4,2-oxathiazolidine, 2,3-dihydro-1H-[1,2,3]triazole,2,5-dihydro-1H-[1,2,3]triazole, 4,5-dihydro-1H-[1,2,3]triazol-1-yl,4,5-dihydro-1H-[1,2,3]triazol-3-yl, 4,5-dihydro-1H-[1,2,3]triazol-5-yl,2,3-dihydro-1H-[1,2,4]triazole, 4,5-dihydro-1H-[1,2,4]triazole,2,3-dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]oxadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thidiazole,2,5-dihydro-[1,2,4]thiadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,5-dihydro-[1,2,4]oxadiazole, 2,3-dihydro-[1,2,4]oxadiazole,4,5-dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4]thiadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,3,4]oxadiazole, 2,3-dihydro-[1,3,4]thiadiazole,[1,4,2]oxathiazole, [1,3,4]oxathiazole, 1,3,5-triazaperhydroine,1,2,4-triazaperhydroine, 1,4,2-dithiazaperhydroine,1,4,2-dioxazaperhydroine, 1,3,5-oxadiazaperhydroine,1,2,5-oxadiazaperhydroine, 1,3,4-thiadiazaperhydroine,1,3,5-thiadiazaperhydroine, 1,2,5-thiadiazaperhydroine,1,3,4-oxadiazaperhydroine, 1,4,3-oxathiazaperhydroine,1,4,2-oxathiazaperhydroine, 1,4,5,6-tetrahydropyridazine,1,2,3,4-tetrahydropyridazine, 1,2,3,6-tetrahydropyridazine,1,2,5,6-tetrahydropyrimidine, 1,2,3,4-tetrahydropyrimidine,1,4,5,6-tetrahydropyrimidine, 1,2,3,6-tetrahydropyrazine,1,2,3,4-tetrahydropyrazine, 5,6-dihydro-4H-[1,2]oxazine,5,6-dihydro-2H-[1,2]oxazine, 3,6-dihydro-2H-[1,2]oxazine,3,4-dihydro-2H-[1,2]oxazine, 5,6-dihydro-4H-[1,2]thiazine,5,6-dihydro-2H-[1,2]thiazine, 3,6-dihydro-2H-[1,2]thiazine,3,4-dihydro-2H-[1,2]thiazine, 5,6-dihydro-2H-[1,3]oxazine,5,6-dihydro-4H-[1,3]oxazine, 3,6-dihydro-2H-[1,3]oxazine,3,4-dihydro-2H-[1,3]oxazine, 3,6-dihydro-2H-[1,4]oxazine,3,4-dihydro-2H-[1,4]oxazine, 5,6-dihydro-2H-[1,3]thiazine,5,6-dihydro-4H-[1,3]thiazine, 3,6-dihydro-2H-[1,3]thiazine,3,4-dihydro-2H-[1,3]thiazine, 3,6-dihydro-2H-[1,4]thiazine,3,4-dihydro-2H-[1,4]thiazine, 1,2,3,6-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,3,5]triazine,2,3,4,5-tetrahydro-[1,2,4]triazine, 1,4,5,6-tetrahydro-[1,2,4]triazine,5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,3,4-dihydro-2H-[1,3,4]oxadiazine, 3,6-dihydro-2H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,3,5]oxadiazine, 3,6-dihydro-2H-[1,3,5]oxadiazine,5,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,2,5]oxadiazine,3,4-dihydro-2H-[1,3,4]thiadiazine, 3,6-dihydro-2H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,3,5]thiadiazine, 3,6-dihydro-2H-[1,3,5]thiadiazine,5,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,2,5]thiadiazine,5,6-dihydro-2H-[1,2,3]oxadiazine, 3,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-2H-[1,2,3]thiadiazine, 3,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,4,5-dihydropyridine, 1,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran,2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,2,5-dihydropyridazine, 4,5-dihydropyridazine, 1,2-dihydropyridazine,1,4-dihydropyrimidin-1-yl, 1,4-dihydropyrimidin-4-yl,1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrirnidin-6-yl,2,3-dihydropyrimidine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine,3,6-dihydropyrimidine, 4,5-dihydropyrazine, 5,6-dihydropyrazine,3,6-dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine,1,4-dithiin, 1,4-dioxin, 2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine,2H-1,3-oxazine, 4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine,4H-1,4-oxazine, 2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine,6H-1,3-thiazine, 4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine,1,4-oxathiin, 2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine,4,5-dihydro-1,2,3-triazine, 1H,6H-1,2,3-triazine,1,2-dihydro-1,2,3-triazine, 2,3-dihydro-1,2,4-triazine,3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine, 3,4-dihydro-1,2,4-triazine,1H,4H-1,2,4-triazine, 5,6-dihydro-1,2,4-triazine,4,5-dihydro-1,2,4-triazine, 2H,5H-1,2,4-triazine,1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine, and 1,4,2-oxathiazine,wherein the heterocycle is optionally vicinally fused with a saturatedor unsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S;

R^(j) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(h)and —NR^(h)R^(h); or R^(j) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(h) and—NR^(h)R^(h); and

R^(k) is hydrogen or —CH₃.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₂₋₆alkyl or C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is a naphthyl substituted by 0, 1, 2 or3 substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is R^(i) substituted by 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(i) is substituted by one substituentselected from halo, C₁₋₄haloalkyl and C₁₋₅alkyl, and additionally by 0,1 or 2 substituents independently selected from R⁵.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁵ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁵ is R¹⁰, C₁₋₈alkyl substituted by 0, 1or 2 substituents selected from R¹⁰, or a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S that is optionally vicinallyfused with a saturated or unsaturated 3- or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, the heterocycle and bridge being substituted by 0, 1, 2 or 3substituents independently selected from R¹⁰; or R¹⁵ is —(CH₂)_(n)phenylsubstituted by 0, 1, 2 or 3 substituents independently selected from H,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), and C₁₋₄alkylsubstituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h),—C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h)and —NR^(h)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁶ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁶ is halo, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, —OC₁₋₃alkyl, —C₁₋₂haloalkyl, —OC₁₋₂haloalkyl orC₁₋₃alkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is

wherein at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is other thanC₁₋₄haloalkyl or halo.

In another embodiment, in conjunction with the novel compoundembodiments above and below, at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴is —OR^(h) or —NR^(h)R^(h).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S, so long as the combination of O and S atoms is not greater than2, wherein each of the carbon atoms of the heterocycle is substituted byH, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(h),—S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —OC₁₋₆alkylC(═O)OR^(h), —NR^(h)R^(h),—NR^(h)C₁₋₄haloalkyl, —NR^(h)C₂₋₆alkylNR^(h)R^(h),—N^(h)C₂₋₆alkylOR^(h), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(h)C₁₋₆alkyl or —NR^(h)C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the heterocycle are substituted by H,—C₁₋₆alkylOR^(h)—C₁₋₆alkyl, —C₁₋₆alkylNR^(h)R^(h),—C₁₋₃alkylC(═O)OR^(h), —C₁₋₃alkylC(═O)NR^(h)R^(h),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(h)C(═O)C₁₋₆alkyl, —C(═O)R^(j)or —C₁₋₃alkylR^(j).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1 or 2 atoms selected from O, Nand S, wherein each of the carbon atoms of the heterocycle issubstituted by H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(h),—S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —OC₁₋₆alkylC(═O)OR^(h), NR^(h)R^(h),—NR^(h)C₁₋₄haloalkyl, —NR^(h)C₂₋₆alkylNR^(h)R^(h),—NR^(h)C₂₋₆alkylOR^(h), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(h)C₁₋₆alkyl or —NR^(h)C(═O)C₁₋₆alkyl; andsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the bridge are substituted by H,—C₁₋₆alkylOR^(h), —C₁₋₆alkyl, —C₁₋₆alkylNR^(h)R^(h),—C₁₋₃alkylC(═O)OR^(h), —C₁₋₃alkylC(═O)NR^(h)R^(h),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(h)C(═O)C₁₋₆alkyl, —C(═O)R^(j)or —C₁₋₃alkylR^(j).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is an 8-, 9-, 10- or 11-memberedbicyclic ring, containing 1, 2, 3 or 4 N atoms and 0, 1 or 2 atomsselected from S and O with the remainder being carbon atoms, whereineach of the carbon atoms of the ring is substituted by H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(h), —S(═O)_(n)C₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h),—OC₁₋₆alkylC(═O)OR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(h)C₁₋₆alkyl or—NR^(h)C(═O)C₁₋₆alkyl; and saturated carbon atoms may be additionallysubstituted by ═O; and any available nitrogen atoms in the ring aresubstituted by H, —C₁₋₆alkylOR^(h), —C₁₋₆alkyl, —C₁₋₆alkylNR^(h)R^(h),—C₁₋₃alkylC(═O)OR^(h), —C₁₋₃alkylC(═O)NR^(h)R^(h),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(h)C(═O)C₁₋₆alkyl, —C(═O)R^(j)or —C₁₋₃alkylR^(j).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is an 8-, 9-, 10- or 11-memberedbicyclic ring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atomsselected from S and O with the remainder being carbon atoms, wherein atleast one of the carbon atoms of the ring is substituted by C₁₋₉alkyl,C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(h), —S(═O)_(n)C₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h),—OC₁₋₆alkylC(═O)OR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(h)C₁₋₆alkyl or—NR^(h)C(═O)C₁₋₆alkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁵ and R⁹ are each independently selectedfrom H, C₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h), —NR^(h)R^(h),—NR^(h)C₁₋₄haloalkyl, —NR^(h)C₂₋₆alkylNR^(h)R^(h),—NR^(h)C₂₋₆alkylOR^(h), —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),—C(═O)NR^(h)R^(h), —NR^(h)C(═O)R^(h), —NR^(h)C(═O)NR^(h)R^(h),—NR^(h)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(h)R^(h),—S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(h)R^(h), —NR^(h)S(═O)₂(C₁₋₆alkyl) and—OC(═O)NR^(h)R^(h).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁶ and R⁸ are each independently selectedfrom H, C₁₋₅alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(h)R^(h), —OC₂₋₆alkylOR^(h), —NR^(h)R^(h),—NR^(h)C₁₋₄haloalkyl, C₂₋₆alkylNR^(h)R^(h) or —NR^(h)C₂₋₆alkylOR^(h),—C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(h)R^(h) and —S(C₁₋₆alkyl).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is independently, at each instance,C₁₋₈alkyl, C₁₋₄haloalkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —NR^(h)R^(h), —NR^(h)C₁₋₄haloalkyl,—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h), —C₁₋₈alkylOR^(h),—C₁₋₆alkylNR^(h)R^(h) or —S(C₁₋₆alkyl).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹⁰ and R¹⁴ are each independently selectedfrom H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h) and C₁₋₄alkylsubstituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)NR^(h)R^(h),—C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹¹ and R¹³ are independently, at eachinstance, selected from H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h),—C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h), —NR^(h)C₂₋₆alkylOR^(h) and C₁₋₄alkylsubstituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h),—C(═NR^(h))NR^(h)R^(h), —OR^(h), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹² is independently, at each instance,selected from H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(h)R^(h), —C(═NR^(h))NR^(h)R^(h), —OR^(h),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(h)R^(h),—OC(═O)N(R^(h))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(h)R^(h),—OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(h)R^(h), —S(═O)₂N(R^(h))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(h))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(h))C(═O)NR^(h)R^(h),—NR^(h)R^(h), —N(R^(h))C(═O)(C₁₋₈alkyl), —N(R^(h))C(═O)O(C₁₋₈alkyl),—N(R^(h))C(═O)NR^(h)R^(h), —N(R^(h))C(═NR^(h))NR^(h)R^(h),—N(R^(h))S(═O)₂(C₁₋₈alkyl), —N(R^(h))S(═O)₂NR^(h)R^(h),—NR^(h)C₂₋₆alkylNR^(h)R^(h) and —NR^(h)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is S.

Another aspect of the invention relates to a compound having thestructure:

wherein:

X is O, S or NR^(m);

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m);

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q);

R³ is H or C₁₋₄alkyl;

R⁵ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c)

R⁶ is, independently at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R⁸ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); and (A) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)R^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (B) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkyl and C₁₋₄alkyl substituted by 1 or 2 groups selectedfrom C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═o)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (C) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination of O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl—C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s),—OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br R⁹ is H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (D) R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) or —NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)phenyl, wherein the phenyl is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₉alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═o)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r) is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)ORs,—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═,)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m)C(═O)OR) ^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S,(═)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (E) R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, 13 C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m),—OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆a —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not unsubstituted phenyl;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR ^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, 80, wherein:

R¹ is

R ² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —s(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C)═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),‘NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C¹⁻⁹alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and Sthat is vicinally fused with a saturated or unsaturated 3- or 4-atombridge containing 0, 1, 2 or 3 atoms elected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the ring and bridge are substitutedby 0, 1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═,)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a phenyl ring that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the bridge carbon atoms are substituted with0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₆alkyl, —O—C₁₋₄haloalkyl, —NR^(m)R^(m) or —NR^(m)—C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₅alkyl, C₁₋₄haloalkyl, I, Br orCl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2or 3 atoms selected from N, O and S, so long as the combination of O andS atoms is not greater than 1, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 substituents independently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, whereinthe carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═,)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(, —S(═O))₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)—OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); [C₁₋₈alkyl, C₁₋₅haloalkyl, I, Br or Cl]

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 1 1-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 0, 1, 2 or 3 atoms selected from O, and Sthat is vicinally fused with a saturated or unsaturated 3- or 4-atombridge containing 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the ring and bridge are substitutedby 0, 1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a phenyl ring that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═,)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋ ₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m)C(═O)R) ^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the bridge carbon atoms are substituted with0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₆alkyl, —O—C₁₋₄haloalkyl, —NR^(m)R^(m) or —NR^(m)—C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₅alkyl, C₁₋₄haloalkyl, I, Br orCl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2or 3 atoms selected from N, O and S, so long as the combination of O andS atoms is not greater than 1, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 substituents independently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, whereinthe carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination of O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl—C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s),—OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C1-8alkyl, C₁₋₅haloalkyl, I or Br;

R⁹ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a heterocycle selected from indole,3H-indole, benzo[b]furan, benzothiophene, 1H-indazole, benzimidazole,benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline,1,2,3,4-tetrahydroquinoline, isoquinoline, cinnoline, phthalazine,quinazoline and quinoxaline, wherein the heterocycle is substituted by0, 1, 2 or 3 substituents independently selected from C₁₋₉alkyl, oxo,C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl, —OC(═O)C₁₋₆alkyl,—C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s, —NR) ^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a heterocycle selected from 6-indole,7-indole, 6-3H-indole, 7-3H-indole, 6-benzo[b]furan, 7-benzo[b]furan,6-benzothiophene, 7-benzothiophene, 6-1H-indazole, 7-1H-indazole,benzimidazole, benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline,7-1,2,3,4-tetrahydroquinoline, 8-1,2,3,4-tetrahydroquinoline,isoquinolin-7-yl, isoquinolin-8-yl, 7-cinnoline, 8-cinnoline,phthalazine, 7-quinazoline, 8-quinazoline and quinoxaline, wherein theheterocycle is substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano,—OR^(m), —S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl—C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s),—OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), ——S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))c(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo,nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m) or —NR^(m)—C₁₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is CR⁸.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m); or

R² is

R² is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m, —SR) ^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m)C(═O)R) ^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m) , —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m),—OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m);

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is —(C(R^(q))₂)_(o)phenyl, wherein thephenyl is substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m) —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m)C(═O)R) ^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m)C(═O)R) ^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r)is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(S) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a phenyl ring that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—C₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m); and the bridgecarbon atoms a substituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is CR^(8.)

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 2, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ isnot unsubstituted phenyl;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₂₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 1, 2 or 3 atoms selected from O, N and S, solong as the combination of O and S atoms is not greater than 1, whereinthe ring is substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m);

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is CR⁸.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is N.

Another aspect of the invention relates to a compound having thestructure:

wherein:

X is O, S or NR^(m);

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m);

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q);

R³ is H or C₁₋₄alkyl;

R⁵ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c)

R⁶ is, independently at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R⁸ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); and (A) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s, —NR)^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groups selectedfrom C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C1-4haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (B) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, and S with the remaining atoms being carbon,so long as the combination of O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m)NR) ^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 1 1-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 substituents independently selectedfrom R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (C) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl—C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s),—OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br R⁹ is H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸or N; or (D) R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) or —NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)phenyl, wherein the phenyl is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(s),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r) is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n)—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n l , —N(R)^(m))S(═O)₂NR^(m)R^(m)—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (E) R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination O andS atoms is not greater than 1, wherein the ring is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not unsubstituted phenyl;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═,)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(50 O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S,(═)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 substituents independently selectedfrom R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and Sthat is vicinally fused with a saturated or unsaturated 3- or 4-atombridge containing 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination O and S atomsis not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m)—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a phenyl ring that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the bridge carbon atoms are substituted with0, I or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₆alkyl, —O—C₁₋₄haloalkyl, —NR^(m)R^(m) or —NR^(m)—C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₅alkyl, C₁₋₄haloalkyl, I, Br orCl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2or 3 atoms selected from N, O and S, so long as the combination O and Satoms is not greater than 1, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 substituents independently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, whereinthe carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R²is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),‘C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); [C₁₋₈alkyl, C₁₋₅haloalkyl, I, Br or Cl]

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 substituents independently selectedfrom R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═,)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and Sthat is vicinally fused with a saturated or unsaturated 3- or 4-atombridge containing 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination O and S atomsis not greater than 2, wherein the ring and bridge are substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a phenyl ring that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—C₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the bridge carbon atoms are substituted with0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₆alkyl, —O—C₁₋₄haloalkyl, —NR^(m)R^(m) or —NR^(m)—C₁₋₄haloalkyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is C₁₋₅alkyl, C₁₋₄haloalkyl, I, Br orCl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2or 3 atoms selected from N, O and S, so long as the combination O and Satoms is not greater than 1, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 substituents independently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R^(o) is a saturated, partially-saturatedor unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, whereinthe carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p).

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl—C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s),—OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br;

R⁹ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and Z is CR⁸ or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a heterocycle selected from indole,3H-indole, benzo[b]furan, benzothiophene, 1H-indazole, benzimidazole,benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline,1,2,3,4-tetrahydroquinoline, isoquinoline, cinnoline, phthalazine,quinazoline and quinoxaline, wherein the heterocycle is substituted by0, 1, 2 or 3 substituents independently selected from C₁₋₉alkyl, oxo,C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl, —OC(═O)C₁₋₆alkyl,—C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a heterocycle selected from 6-indole,7-indole, 6-3H-indole, 7-3H-indole, 6-benzo[b]furan, 7-benzo[b]furan,6-benzothiophene, 7-benzothiophene, 6-1H-indazole, 7-1H-indazole,benzimidazole, benzthiazole, 1H-benzotriazole, 7-quinoline, 8-quinoline,7-1,2,3,4-tetrahydroquinoline, 8-1,2,3,4-tetrahydroquinoline,isoquinolin-7-yl, isoquinolin-8-yl, 7-cinnoline, 8-cinnoline,phthalazine, 7-quinazoline, 8-quinazoline and quinoxaline, wherein theheterocycle is substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano,—OR^(m), —S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl, —NR^(m)C(═O)C₁₋₆alkyl—C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s),—OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),'N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), 13 C(═NR^(m))NR^(m)R⁵, —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo,nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m) or —NR^(m)—C₁₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is CR⁸.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m); or

R² is

R² is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—C₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O'C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m),—OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m);

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is —(C(R^(q))₂)_(o)phenyl, wherein thephenyl is substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═,)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m).

In another embodiment, in conjunction with the novel compoundembodiments above and below, R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r)is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))s(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a phenyl ring that is vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination O and S atoms is not greater than 2,wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m); and the bridgecarbon atoms are substituted with 0, 1 or 2 ═O groups.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁷ is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁹ is H.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is CR⁸.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination O andS atoms is not greater than 2, wherein the ring is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═,)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ isnot unsubstituted phenyl;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

In another embodiment, in conjunction with the novel compoundembodiments above and below, R⁴ is a saturated or unsaturated 5- or6-membered ring containing 1, 2 or 3 atoms selected from O, N and S, solong as the combination O and S atoms is not greater than 1, wherein thering is substituted by 0, 1, 2 or 3 substituents independently selectedfrom C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —C₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) and —NR^(m)C₂₋₆alkylOR^(m);

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is CR⁸.

In another embodiment, in conjunction with the novel compoundembodiments above and below, Z is N.

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound having thestructure:

wherein:

R¹ is

or a naphthyl or saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and thenaphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or3 substituents independently selected from R^(5,) R⁶ and R⁷;

R² is H, hydroxy, halo, C₁₋₆alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷; or R¹ and R² together are

R³ is H or C₁₋₄alkyl; or R¹ and R³ together are

R⁴ is

R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is optionallyvicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination O and S atomsis not greater than 2, wherein the carbon atoms of the heterocycle andbridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl; or R⁴is 10-membered bicyclic ring comprising fused 6-membered rings,containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbonatoms, with at least one of the 6-membered rings being aromatic, whereinthe carbon atoms are substituted by H, halo, OR^(a), NR^(a)R^(a),C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbon atoms may beadditionally substituted by ═O;

R⁵ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a—C) ₁₋₆alkylNR^(a)R^(a) or—NR^(a)C₁₋₆alkylOR^(a); or R⁵ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S;

R⁶ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a); or R⁵ and R⁶ together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination O and S atoms is not greater than 2, wherein the carbonatoms of the bridge are substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₆alkyl, (═O), —OC₁₋₆alkyl, —NR^(a)C₁₋₆alkyl,—C₁₋₆alkylOR^(a) and C₁₋₆alkylNR^(a)R^(a), and the available N atoms ofthe bridge are substituted by R^(a), —C₁₋₆alkylOR^(a) orC₁₋₆alkylNR^(a)R^(a);

R⁷ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a);

R⁸ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a); or R⁷ and R⁸ together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination O and S atoms is not greater than 2, wherein the carbonatoms of the bridge are substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₆alkyl, (═O), —O—C₁₋₆alkyl, —NR^(a)C₁₋₆alkyl,—C₁₋₆alkylOR^(a) and C₁₋₆alkylNR^(a)R^(a), and the available N atoms ofthe bridge are substituted by R^(a), —C₁₋₆alkylOR^(a) orC₁₋₆alkylNR^(a)R^(a);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a);

R¹⁰ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹¹ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylR^(c),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; or R¹⁰and R¹¹ together are a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination O and S atomsis not greater than 2, wherein the each of the carbon atoms in thebridge is substituted by H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl,—NR^(a)R^(a), —C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); wherein if R¹⁰, R^(12,) R¹³ and R¹⁴ are all H, thenR¹¹ is not —O—C₁₋₆alkylNR^(a)R^(a) or —O—C₁₋₆alkylOR^(a);

R¹² is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; or R¹¹ and R¹² together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination O and S atoms is not greater than 2, wherein the each of thecarbon atoms in the bridge is substituted by H, ═O, —OR^(a),—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a), —C₁₋₆alkylNR^(a)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl, —NR^(a)C(═O)C₁₋₆alkyl,—C₁₋₃alkylOC(═O)C₁₋₆alkyl or —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(a),—C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c);

R¹³ is independently, at each instance, H, C¹⁻⁹alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹⁴ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R^(a) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl;

R^(c) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(c) is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the carbon atoms of the heterocycle aresubstituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fusedphenyl ring is substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a);

L¹ is a bond, —CH₂CH₂— or —CH═CH—;

L² is NR^(a), O, S(═O)_(n), —N═CH—, —CH₂NR^(a)—, —CH═N— or —NR^(a)CH₂—;

X is O, S or NR^(a); or X and R² together are ═N—CH═CH—, ═C—O—, ═C—S—,or ═C—NR^(a)—;

Y is NH or O; and

n is independently, at each instance, 0, 1 or 2; with the proviso thatwhen R¹ is 4-chlorophenyl, then R⁴ is not 3-methoxyphenyl.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R¹ is

or a naphthyl or saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and thenaphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or3 substituents independently selected from R⁵, R⁶ and R⁷;

R² is H, hydroxy, halo, C₁₋₆alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷; and

R³ is H or C₁₋₄alkyl.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R¹ is

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁷ is independently, at each instance,C₂₋₉alkyl or C₁₋₄haloalkyl.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R¹ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶ and R⁷.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R² is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶and R⁷.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R² is

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R² is

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R² is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶ and R⁷.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R¹ and R² together are

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R¹ and R³ together are

In another embodiment, in conjunction with the method of treatmentembodiments above and below, X and R² together are ═N—CH═CH—, ═C—O—,═C—S—, or ═C—NR^(a)—.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl—O—R^(a); and

Y² is —NR^(a)— or —O—.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0 or 1 atoms independently selected from O, N andS, wherein the each of the carbon atoms in the bridge is substituted byH, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl—O—R^(a); and

Y² is —NR^(b)— or —O—.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl—O—R^(a); and

Y² is —NR^(b)— or —O—.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═N)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃akylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl—O—R^(a); and

Y² is —NR^(b)— or —O—.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl—O—R^(a); and

Y² is —NR^(a)— or —O—.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is 10-membered bicyclic ring comprisingfused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with theremainder being carbon atoms, with at least one of the 6-membered ringsbeing aromatic, wherein the carbon atoms are substituted by H, halo,OR^(a), NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbonatoms may be additionally substituted by ═O.

In another embodiment, in conjunction with the method of treatmentembodiments above and below, R⁴ is

R¹⁰ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a), —C₁₋₆alkylOR^(a),—C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl,—C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl;

R¹¹ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylR^(c),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl;C₁₋₆alkylNR^(a)R^(a);

R¹² is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)^(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆akylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl;

R¹³ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; and

R¹⁴ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; wherein one of R¹⁰ and R¹² is not H.

In another embodiment, in conjunction with the method of treatmentembodiments above, R⁴ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 heteroatoms independently selectedfrom N, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄haloalkyl, —OR^(a) and—NR^(a)R^(a).

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according tocompound description embodiments above—each seperately andalternatively.

Another aspect of the invention involves a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound having thestructure:

wherein:

X is O, S or NR^(m);

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m);

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q);

R³ is H or C₁₋₄alkyl;

R⁵ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c)

R⁶ is, independently at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R⁸ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); and (A) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR, —C(═O)NR^(m)R^(s),C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (B) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m)S(═O)) ₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (C) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination of O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl,—NR^(m)C(═O)C₁₋₆alkyl-C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br R⁹ is H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (D) R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) or —NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)phenyl, wherein the phenyl is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r) is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m)S(═O)) ₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (E) R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(n), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(n),—NR^(m)C₂₋₆alkylNR^(m)R^(n), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not unsubstituted phenyl;

R⁷ is C₂₋₆alkyl, C₁₋₅haloalkyl, I or Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

Another aspect of the invention involves a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound having thestructure:

wherein:

X is O, S or NR^(m);

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R , —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m);

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q);

R³ is H or C₁₋₄alkyl;

R⁵ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c)

R⁶ is, independently at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R⁸ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); and (A) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(n), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(n),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR_(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or-NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR , —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (B) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S (═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (C) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination of O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl,—NR^(m)C(═O)C₁₋₆alkyl-C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br R⁹ is H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (D) R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) or —NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)phenyl, wherein the phenyl is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r) is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R)C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m)C(═O)OR) ^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m)C(═O)NR) ^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (E) R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not unsubstituted phenyl;

R⁷ is C₂₋₆alkyl, C₁₋₅haloalkyl, I or Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O-C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

Another aspect of the invention involves a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention involves the use of any of the abovecompound embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording the any one of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders.

Another aspect of the invention relates to the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders, wherein the medicamentcontains a compound having the structure:

wherein:

X is O, S or NR^(m);

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))N^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m);

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q);

R³ is H or C₁₋₄alkyl;

R⁵ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c)

R⁶ is, independently at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R⁸ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); and (A) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (B) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (C) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination of O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl,—NR^(m)C(═O)C₁₋₆alkyl-C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(n), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br R⁹ is H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (D) R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m) or —NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)phenyl, wherein the phenyl is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋ ₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r) is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (E) R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m).—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not unsubstituted phenyl;

R⁷ is C₂₋₆alkyl, C₁₋₅haloalkyl, I or Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

Another aspect of the invention relates to the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders, wherein the medicamentcontains a compound having the structure:

wherein:

X is O, S or NR^(m);

n is independently, at each instance, 0, 1 or 2;

o is independently, at each instance, 0, 1, 2 or 3;

R^(m) is independently at each instance H or R^(n);

R^(n) is independently at each instance C₁₋₈alkyl, phenyl or benzyl;

R^(q) is independently in each instance H, C₁₋₄alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m);

R^(s) is R^(n) substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(q);

R³ is H or C₁₋₄alkyl;

R⁵ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c)

R⁶ is, independently at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R⁸ is H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m); and (A) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (B) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m),—NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

R^(o) is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, so long asthe combination of O and S atoms is not greater than 2, wherein thecarbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(p);

R^(p) is independently at each instance C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); and

Y is O or NH; or (C) R¹ is

R² is H, —OR^(m), halo, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated, partially-saturated or unsaturated 8-, 9-, 10 or11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atomsselected from O, N and S, so long as the combination of O and S atoms isnot greater than 2, but excluding quinolin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₉alkyl, oxo, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(m),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(m)R^(m),—O—C₁₋₆alkylOR^(m), —NR^(m)R^(m), —NR^(m)—C₁₋₄haloalkyl,—NR^(m)—C₁₋₆alkylNR^(m)R^(m), —NR^(m)—C₁₋₆alkylOR^(m), —C(═O)C₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(m)C₁₋₆alkyl,—NR^(m)C(═O)C₁₋₆alkyl-C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not2-aminocarbonylmethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl,2-cyanomethyl-2,3-dihydro-benzo[1,4]dioxin-8-yl, quinolin-3-yl,3H-quinazolin-4-on-3-yl, benzo[1,3]dioxol-5-yl,3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl or4,4-dimethyl-3,4-dihydro-1H-quinolin-2-on-7-yl;

R⁷ is C₁₋₈alkyl, C₁₋₅haloalkyl, I or Br R⁹ is H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m),—NR^(m)—C₁₋₆alkylOR^(m), or —(CH₂)_(n)R^(c);

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (D) R¹ is

R² is C₁₋₆alkyl substituted by 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m) or—NR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)phenyl, wherein the phenyl is substituted by 0, 1,2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) andNR^(m)C₂₋₆alkylOR^(m); or

R² is —(C(R^(q))₂)_(o)R^(r), wherein R^(r) is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n),—C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n),—OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m),—OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n), —S(═O)₂R^(n),—S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m);

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the ring and bridge are substituted by 0, 1, 2 or 3substituents independently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(n), —C(═O)OR^(n), —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(m), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m),—SR^(m), —S(═O)R^(n), —S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m),—S(═O)₂N(R^(m))C(═O)R^(n), —S(═O)₂N(R^(m))C(═O)OR^(n),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(m), —NR^(m)R^(m), —N(R^(m))C(═O)R^(n),—N(R^(m))C(═O)OR^(n), —N(R^(m))C(═O)NR^(m)R^(m),—N(R^(m))C(═NR^(m))NR^(m)R^(m), —N(R^(m))S(═O)₂R^(n),—N(R^(m))S(═O)₂NR^(m)R^(m), —NR^(m)C₂₋₆alkylNR^(m)R^(m),—NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s), —C(═O)OR^(s), —C(═O)NR^(m)R^(s),—C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s), —OC(═O)NR^(m)R^(s),—OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s),—SR^(s), —S(═O)R^(s), —S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s),—S(═O)₂N(R^(m))C(═O)R^(s), —S(═O)₂N(R^(m))C(═O)OR^(s),—S(═O)₂N(R^(m))C(═O)NR^(m)R^(s), —NR^(m)R^(s), —N(R^(m))C(═O)R^(s),—N(R^(m))C(═O)OR^(s), —N(R^(m))C(═O)NR^(m)R^(s),—N(R^(m))C(═NR^(m))NR^(m)R^(s), —N(R^(m))S(═O)₂R^(s),—N(R^(m))S(═O)₂NR^(m)R^(s), —NR^(m)C₂₋₆alkylNR^(m)R^(s),—NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkyl substituted by 1 or 2 groupsselected from C₁₋₂haloalkyl, halo, cyano, nitro, —C(═O)R^(n),—C(═O)OR^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m), and the ring and bridge carbon atoms aresubstituted with 0, 1 or 2 ═O groups;

R⁷ is C₂₋₈alkyl, C₁₋₅haloalkyl, I, Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N; or (E) R¹ is

R² is H, —OR^(m), Cl, C₁₋₃haloalkyl or C₁₋₆alkyl;

R⁴ is a saturated or unsaturated 5- or 6-membered ring containing 0, 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 1, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)NR^(m)R^(m),—C(═NR^(m))NR^(m)R^(m), —OR^(n), —OC(═O)R^(n), —OC(═O)NR^(m)R^(m),—OC(═O)N(R^(m))S(═O)₂R^(n), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —NR^(m)C₂₋₆alkylOR^(m), —C(═O)R^(s),—C(═O)OR^(s), —C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s),—OC(═O)R^(s), —OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s),—OC₂₋₆alkylNR^(m)R^(s), —OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s),—S(═O)₂R^(s), —S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and C₁₋₄alkylsubstituted by 1 or 2 groups selected from C₁₋₂haloalkyl, halo, cyano,nitro, —C(═O)R^(n), —C(═O)NR^(m)R^(m), —C(═NR^(m))NR^(m)R^(m), —OR^(m),—OC(═O)R^(n), —OC(═O)NR^(m)R^(m), —OC(═O)N(R^(m))S(═O)₂R^(n),—OC₂₋₆alkylNR^(m)R^(m), —OC₂₋₆alkylOR^(m), —SR^(m), —S(═O)R^(n),—S(═O)₂R^(n), —S(═O)₂NR^(m)R^(m), —S(═O)₂N(R^(m))C(═O)R^(n),—S(═O)₂N(R^(m))C(═O)OR^(n), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(m),—NR^(m)R^(m), —N(R^(m))C(═O)R^(n), —N(R^(m))C(═O)OR^(n),—N(R^(m))C(═O)NR^(m)R^(m), —N(R^(m))C(═NR^(m))NR^(m)R^(m),—N(R^(m))S(═O)₂R^(n), —N(R^(m))S(═O)₂NR^(m)R^(m),—NR^(m)C₂₋₆alkylNR^(m)R^(m), —C(═O)R^(s), —C(═O)OR^(s),—C(═O)NR^(m)R^(s), —C(═NR^(m))NR^(m)R^(s), —OR^(s), —OC(═O)R^(s),—OC(═O)NR^(m)R^(s), —OC(═O)N(R^(m))S(═O)₂R^(s), —OC₂₋₆alkylNR^(m)R^(s),—OC₂₋₆alkylOR^(s), —SR^(s), —S(═O)R^(s), —S(═O)₂R^(s),—S(═O)₂NR^(m)R^(s), —S(═O)₂N(R^(m))C(═O)R^(s),—S(═O)₂N(R^(m))C(═O)OR^(s), —S(═O)₂N(R^(m))C(═O)NR^(m)R^(s),—NR^(m)R^(s), —N(R^(m))C(═O)R^(s), —N(R^(m))C(═O)OR^(s),—N(R^(m))C(═O)NR^(m)R^(s), —N(R^(m))C(═NR^(m))NR^(m)R^(s),—N(R^(m))S(═O)₂R^(s), —N(R^(m))S(═O)₂NR^(m)R^(s),—NR^(m)C₂₋₆alkylNR^(m)R^(s), —NR^(m)C₂₋₆alkylOR^(s) and—NR^(m)C₂₋₆alkylOR^(m); wherein R⁴ is not unsubstituted phenyl;

R⁷ is C₂₋₆alkyl, C₁₋₅haloalkyl, I or Br;

R⁹ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(m)R^(m), —O—C₁₋₆alkylOR^(m), —NR^(m)R^(m),—NR^(m)—C₁₋₄haloalkyl, —NR^(m)—C₁₋₆alkylNR^(m)R^(m) or—NR^(m)—C₁₋₆alkylOR^(m);

Y is NH; and

Z is CR⁸ or N.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alkyl” means an alkyl group comprising from α to β carbon atomsin a branched, cyclical or linear relationship or any combination of thethree. The alkyl groups described in this section may also contain adouble or triple bond. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Halo” means a halogen atoms selected from F, Cl, Br and I.

“C_(α-β)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can beused to protect the same amino group, such as a primary amino group canbe protected by both an aralkyl group and an aralkoxycarbonyl group.Amino protecting groups can also form a heterocyclic ring with thenitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.Amino groups may also be protected against undesired reactions, such asoxidation, through the formation of an addition salt, such ashydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.Many of the amino protecting groups are also suitable for protectingcarboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkylgroups are also suitable groups for protecting hydroxy and mercaptogroups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydroylsis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

Experimental

General

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in Degrees centigrade unless otherwise indicated.All compounds showed NMR spectra consistent with their assignedstructures. Melting points were determined on a Buchi apparatus and areuncorrected. Mass spectral data was determined by electrosprayionization technique. All examples were purified to >95% purity asdetermined by high-performance liquid chromatography (HPLC). Unlessotherwise stated, reactions were run at room temperature.

The following abbreviations are used:

-   aq.—aqueous-   cond—concentrated-   DMF—N,N-dimethylformamide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   EtOH—ethyl alcohol-   h—hour-   min—minutes-   MeOH—methyl alcohol-   satd—saturated-   THF—tetrahydrofuran

EXAMPLE 1

(2E)-3-[4-(tert-Butyl)phenyl]-N-phenylprop-2-enamide. To a 10 mL glassvial was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol,EMKA-Chemie) followed by CH₂Cl₂ (5 mL),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg,1.17 mmol, Bachem) and aniline (98 uL, 100 mg, 1.08 mmol, Aldrich). Thereaction mixture was magnetically stirred at 25° C. for 24 h. EtOAc wasadded (60 mL) and the mixture washed successively with 1 N NaOH (2×20mL), 1 N HCl (20 mL), water (20 mL) and satd NaCl (20 mL), dried overMgSO₄, filtered and concentrated. Recrystallization from hexane andCH₂Cl₂ provided the title product as white crystals. MP 141° C. MS (ESI,pos. ion) m/z: 280 (M+1).

EXAMPLE 2

(2E)-N-(3,4-Dimethoxyphenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide

To a 20 mL round-bottomed flask equipped with reflux condenser anddrying tube was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98mmol, EMKA-Chemie) followed by CH₂Cl₂ (5 mL), oxalyl chloride (90 uL,130 mg, 1.03 mmol, Aldrich) and DMF (1 uL). The reaction mixture wasmagnetically stirred and heated at reflux for 30 min. The reactionmixture was concentrated in vacuo and the residue dissolved in acetone(2 mL). The solution was added to a mixture of 3,4-dimethoxyaniline (180mg, 1.17 mmol, Aldrich), potassium carbonate (200 mg), water (2 mL) andacetone (2 mL), magnetically stirred at 25° C. in a 10 mL glass vial.The reaction mixture was stirred at 25° C. for 16 h then diluted withEtOAc (60 mL) and washed successively with 1 N HCl (20 mL), 1 N NaOH (20mL), water (20 mL) and satd NaCl (20 mL), dried over MgSO₄, filtered andconcentrated. Recrystallization from hexane and CH₂Cl₂ provided thetitle product as a yellow solid. MP 115-116° C. MS (ESI, pos. ion) m/z:340 (M+1).

EXAMPLE 3

(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-hydroxy-3-methoxyphenyl)prop-2-enamide

(a). 4-Amino-2-methoxyphenol. To a round-bottomed flask was added4-nitroguaiacol (500 mg, 3.0 mmol, Aldrich) and anhydrous EtOH (50 mL).The solution was stirred magnetically under N₂ and treated with 10% Pdon carbon (200 mg, Aldrich). The suspension was purged with H₂ and thenstirred at 25° C. under 1 atm H₂ for 16 h. The suspension was purgedwith N₂, filtered through Celite and concentrated in vacuo to provide adark solid. The solid was washed with 1:1 CH₂Cl₂:hexane and dried invacuo to provide the title product as pale brown crystals. MS (ESI, pos.ion) m/z: 140 (M+1).

(b).(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-hydroxy-3-methoxyphenyl)prop-2-enamide.Analogous to the procedure used to prepare Example 2,4-amino-2-methoxyphenol, Example 3(a), (164 mg, 1.18 mmol) and4-t-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided,after recrystallization of the crude product from CH₂Cl₂ and hexane, thetitle product as brown crystals. MP 203-204° C. MS (ESI, pos. ion) m/z:326 (M+1).

EXAMPLE 4

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-5,6,7,8-tetrahydronaphthyl)prop-2-enamide

(a). 2-5,6,7,8-Tetrahydronaphthylamine. To a round-bottomed flask wasadded 6-amino-1,2,3,4-tetrahydronaphthalene (500 mg, 3.10 mmol,Maybridge), triethylsilane (2.50 mL, 15.5 mmol, Aldrich) andtrifluoroacetic acid (5.0 mL, 66 mmol, Aldrich). The reaction mixturewas magnetically stirred vigorously, at 25° C., for 2 h. The solventswere removed in vacuo and the residue dissolved in EtOAc (50 mL) andextracted with 1 N HCl (100 mL, then 50 mL). The combined aqueous acidicextract was washed with EtOAc (50 mL) then basified with 5 N NaOH, at 0°C., to pH 10. The mixture was extracted with CH₂Cl₂ (3×50 mL), thecombined organic extract washed with water (50 mL), satd NaCl (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to provide thetitle product as a brown oil. MS (ESI, pos. ion) m/z: 148 (M+1).

(b).(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-5,6,7,8-tetrahydronaphthyl)prop-2-enamide.Analogous to the procedure used to prepare Example 2,2-5,6,7,8-tetrahydronaphthylamine, Example 4(a), (173 mg, 1.18 mmol) and4-t-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided,after purification by silica gel chromatography (4:1 hexane:EtOAc)followed by recrystallization from CH₂Cl₂ and hexane, the title productas white crystals. MP 198-199° C. MS (ESI, pos. ion) m/z: 334 (M+1).

EXAMPLE 5

(2E)-N-(2H,3H,4H-Benzo[3,4-e]1,4-oxazaperhydroin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) 2H,3H,4H-Benzo[e]1,4-oxazaperhydroine-6-ylamine. To a round-bottomedflask was added 2-amino-4-nitrophenol (1.0 g, 6.5 mmol, Aldrich),potassium carbonate (1.8 g, 13 mmol), DMF (5 mL) and 1,2-dibromoethane(0.59 mL, 6.9 mmol, Aldrich). The mixture was magnetically stirred andheated in a 125° C. oil bath, under N₂, for 2.5 h. After allowing tocool to 25° C., the reaction mixture was diluted with EtOAc (100 mL),washed with 1 N NaOH (3×50 mL), water (50 mL), satd NaCl (50 mL), driedover Na₂SO₄, filtered and concentrated to provide a dark residue [MS(ESI, pos. ion) m/z: 181 (M+1)]. The crude product was dissolved in EtOH(100 mL), the solution was purged with N₂, treated with 10% Pd on carbon(450 mg, Aldrich), purged with H₂then magnetically stirred under 1 atmH₂ for 2 h. After purging again with N₂, the suspension was filteredthrough Celite and concentrated in vacuo. Purification by silica gelchromatography (95:5 CH₂Cl₂:2 M NH₃ in EtOH) provided the title productas a viscous brown oil. MS (ESI, pos. ion) m/z: 151 (M+1).

(b)(2E)-N-(2H,3H,4H-Benzo[3,4-e]1,4-oxazaperhydroin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 2,2H,3H,4H-benzo[e]1,4-oxazaperhydroine-6-ylamine, Example 5(a), (176 mg,1.18 mmol) and 4-t-butyl-trans-cinnamic acid (200 mg, 0.98 mmol,EMKA-Chemie) provided, after purification by silica gel chromatography(step gradient, 6:3:1 CH₂Cl₂:hexane:EtOAc then 9:1 hexane:EtOAc) thetitle product as a yellow solid. MP 108-114° C. MS (ESI, pos. ion) m/z:337 (M+1).

EXAMPLE 6

(2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[3,4-e]1,4-oxazaperhydroin-6-yl))prop-2-enamide

(a) 6-Nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one. A mixture of4-nitro-2-aminophenol (4.6 g, 30 mmol, Aldrich), benzyltrimethylammoniumchloride (6.8 g, 30 mmol, Aldrich) and solid NaHCO₃ (12.6 g, 150 mmol)in chloroform (100 mL) was magnetically stirred at 0° C. in around-bottomed flask and treated dropwise with chloroacetyl chloride(2.9 mL, 33 mmol, Aldrich) over a period of 30 min. After the additionwas complete, the reaction mixture was stirred at 0° C. for 1 h, then at50° C. overnight. The solvent was removed in vacuo and the residuetreated with water (50 mL), collected by filtration and washed withwater. The solid was recrystallized from EtOH to provide6-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one. MS (ESI, neg. ion) m/z:193 (M−1).

(b) 6-Amino-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one. To a suspension of6-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 6(a), (0.50 g,2.6 mmol) and CuCl (0.77 g, 7.8 mmol, Aldrich) in anhydrous MeOH (25mL), magnetically stirred at 25° C. in a round-bottomed flask, was addedpotassium borohydride (0.98 g, 18 mmol, Aldrich) in portions. Thereaction mixture was stirred at 25° C. for 0.5 h, then the solvent wasremoved in vacuo and the residue suspended in water (30 mL) andextracted with EtOAc (5×20 mL). The combined organic extracts werewashed with satd NaCl, dried over Na₂SO₄, filtered and concentrated invacuo to provide the title product as a brown solid.

MS (ESI, pos. ion) m/z: 165 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[3,4-e]1,4-oxazaperhydroin-6-yl))prop-2-enamide.Analogous to the procedure used to prepare Example 1,6-amino-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 6(b), (207 mg,1.26 mmol) and 4-tert-butyl-trans-cinnamic acid (258 mg, 1.26 mmolEMKA-Chemie) provided, after recrystallization from EtOAc and hexane,the title compound as a pale yellow solid. MP>280° C. MS (ESI, pos. ion)m/z: 351 (M+1).

EXAMPLE 7

(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[3,4-e]1,4-oxazaperhydroin-6-yl))prop-2-enamide

(a) 4-Methyl-6-nitro-2H-benzo[e]1,4-oxazaperhydroin-3-one. A mixture of6-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 6(a), (970 mg,25 mmol), benzyltrimethylammonium chloride (114 mg, 0.50 mmol, Aldrich)and iodomethane (0.47 mL, 7.5 mmol, Aldrich) in CH₂Cl₂ (20 mL) wasstirred magnetically in a 100 mL round-bottomed flask and treated withCsOH monohydrate (4.2 g, 25 mmol, Aldrich). The reaction mixture wasstirred at 25° C. for 1 h, treated with water (5 mL) and extracted withCH₂Cl₂ (3×50 mL). The combined organic extract was washed with water (5mL), satd NaCl (5 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (9:1hexane:EtOAc) to provide the title product.

MS (ESI, pos. ion) m/z: 209 (M+1).

(b) 6-Amino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one. To a solutionof 4-methyl-6-nitro-2H-benzo[e]1,4-oxazaperhydroin-3-one, Example 7(a),(700 mg, 3.4 mmol) and NiCl₂.6H₂O (400 mg, 1.7 mmol, Aldrich) in MeOH(10 mL), magnetically stirred in a 100 mL round-bottomed flask at 25°C., was added NaBH₄ (190 mg, 5.1 mmol, Aldrich) in portions. Thereaction mixture was stirred for 30 min then concentrated in vacuo.Purification by silica gel chromatography (CH₂Cl₂/EtOAc) provided thetitle product. MS (ESI, pos. ion) m/z: 179 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[3,4-e]1,4-oxazaperhydroin-6-yl))prop-2-enamide.Analogous to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and6-amino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one, Example 7(b),(180 mg, 1.0 mmol) provided, after purification by silica gelchromatography (4:1 CH₂Cl₂:EtOAc), the title product as a pale yellowsolid. MP 201-203° C. MS (ESI, pos. ion) m/z: 365 (M+1).

EXAMPLE 8

(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl(2H,3H-benzo[3,4-e]1,4-oxazaperhydroin-6-yl))prop-2-enamide

To a solution of lithium aluminum hydride (2.0 mL, 2.0 mmol, 1.0 M inTHF, Aldrich), magnetically stirred at 0° C. in a round-bottomed flaskunder N₂, was added6-amino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one, Example 7b, (180mg, 1.0 mmol). The reaction mixture was allowed to warm to 25° C. andstirred at that temperature for 1 h. The reaction was quenched by thedropwise addition of 20% H₂O/THF (1.2 mL), followed by 5 N NaOH (0.2mL). The mixture was stirred at 25° C. for 30 min, then filtered andwashed with EtOAc.

The filtrate was dried over Na₂SO₄, filtered and concentrated in vacuo[MS (ESI, pos. ion) m/z: 165 (M+1)]. Analogous to the procedure used toprepare Example 1, the crude product and 4-tert-butyl-trans-cinnamicacid provided the title compound as a pale yellow solid. MP 186-188° C.MS (ESI, pos. ion) m/z: 351 (M+1).

EXAMPLE 9

(2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[e]1,4-oxazaperhydroin-7-yl))prop-2-enamide

(a) 7-Nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one. Analogous to theprocedure used for the preparation of6-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 6(a),5-nitro-2-aminophenol (4.6 g, 30 mmol, Aldrich) and chloroacetylchloride (2.9 mL, 33 mmol, Aldrich) provided, after recrystallizationfrom EtOH, 7-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one.

MS (ESI, neg. ion) m/z: 193 (M−1).

(b) 7-Amino-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one. A mixture of7-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 9(a), (970 mg,5.0 mmol) and 10% Pd on carbon (100 mg, Aldrich) in MeOH (20 mL) wasmagnetically stirred in a round-bottomed flask under 1 atm H₂ for 2 h.The mixture was purged with N₂ and filtered through a pad of Celite.Concentration in vacuo provided the title product. MS (ESI, pos. ion)m/z: 165 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[e]1,4-oxazaperhydroin-7-yl))prop-2-enamide.Analogous to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and7-amino-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 9(b), (164 mg,1.0 mmol) provided, after purification by silica gel chromatography (4:1CH₂Cl₂:EtOAc), the title product as a pale yellow solid. MP 226-227° C.MS (ESI, pos. ion) m/z: 351 (M+1).

EXAMPLE 10

(2E)-N-(2H,3H,4H-Benzo[e]1,4-oxazaperhydroin-7-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide

To a solution of borane-THF complex (2.5 mL, 2.5 mmol, 1.0 M in THF,Aldrich), magnetically stirred at 0° C. under N₂ in a round-bottomedflask equipped with a reflux condenser, was added7-amino-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 9(b), (160 mg,1.0 mmol). The reaction mixture was stirred at reflux for 2 h, thentreated with EtOH (0.5 mL) and reflux continued for an additional 1 h.The mixture was treated with cond HCl (0.5 mL) and reflux continued foran additional 1 h. The solvent was removed in vacuo and the residuetreated with 1 N NaOH (5 mL) and extracted with CH₂Cl₂ (3×20 mL). Thecombined organic extracts were washed with satd NaCl, dried over Na₂SO₄,filtered and concentrated in vacuo to provide the crude aniline [MS(ESI, pos. ion) m/z: 151 (M+1)]. Analogous to the procedure used toprepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol,EMKA-Chemie) and the crude aniline, after purification by silica gelchromatography (85:15 CH₂Cl₂:EtOAc), provided the title product as apale yellow solid. MP 186-188° C. MS (ESI, pos. ion) m/z: 337 (M+1).

EXAMPLE 11

(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[e]1,4-oxazaperhydroin-7-yl))prop-2-enamide

(a) 4-Methyl-7-nitro-2H-benzo[e]1,4-oxazaperhydroin-3-one. Analogous tothe procedure used to prepare Example 7(a),7-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 9(a), (970 mg,25 mmol), benzyltrimethyl-ammonium chloride (110 mg, 0.50 mmol,Aldrich), iodomethane (0.47 mL, 7.5 mmol, Aldrich) and CsOH hydrate (4.2g, 25 mmol, Aldrich), after purification by silica gel chromatography(9:1 hexane:EtOAc), provided the title product. MS (ESI, neg. ion) m/z:207 (M−1).

(b) 7-Amino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one. Analogous tothe procedure used to prepare Example 3(a),4-methyl-7-nitro-2H-benzo[e]1,4-oxazaperhydroin-3-one, Example 11(a),(1.0 g, 5.0 mmol) provided, after recrystallization from EtOH, the titleproduct. MS (ESI, pos. ion) m/z: 179 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[e]1,4-oxazaperhydroin-7-yl))prop-2-enamide.Analogous to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and7-amino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one, Example 11b, (164mg, 1.0 mmol) provided, after purification by silica gel chromatography(85:15 CH₂Cl₂:EtOAc), the title product as a pale yellow solid. MP194-195° C. MS (ESI, pos. ion) m/z: 365 (M+1).

EXAMPLE 12

(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl(2H,3H-benzo[e]1,4-oxazaperhydroin-7-yl))prop-2-enamide

Analogous to the procedure used for the preparation of Example 10,7-amino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one, Example 11(b),(180 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0mmol, EMKA-Chemie) provided, after purification by silica gelchromatography (85:15 CH₂Cl₂:EtOAc), the title product as a pale yellowsolid. MP 232-233° C. MS (ESI, pos. ion) m/z: 351 (M+1).

EXAMPLE 13

Ethyl6-{(2E)-3-[4-(tert-butyl)phenyl]prop-2-enoylamino}-2H,3H,4H-benzo[e]1,4-oxazaperhydroine-2-carboxylate

(a) Ethyl 6-nitro-2H,3H,4H-benzo[e]1,4-oxazaperhydroine-2-carboxylate. Asolution of ethyl 2,3-dibromopropionate (4.8 mL, 33 mmol, Aldrich) inacetone (10 mL, Aldrich) was added to a mixture of 2-amino-4-nitrophenol(4.6 g, 30 mmol, Aldrich) in 80 mL of acetone in a 150 mL round-bottomedflask at 25° C. After the addition, the mixture was stirred at 60° C.for 48 h. The solvent was removed in vacuo, and the residue was treatedwith water (30 mL) and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic phases were washed with satd NaCl (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (9:1 CH₂Cl₂:EtOAc) to give the title product. MS(ESI, pos. ion) m/z: 253 (M+1).

(b) Ethyl 6-amino-2H,3H,4H-benzo[e]1,4-oxazaperhydroine-2-carboxylate.Analogous to the procedure used to prepare Example 3(a), ethyl6-nitro-2H,3H,4H-benzo[e]1,4-oxazaperhydroine-2-carboxylate, Example13(a), (1.3 g, 5.0 mmol) provided the title product. MS (ESI, pos. ion)m/z: 223 (M+1). (c). Analogous to the procedure used to prepare Example1, 4-tert-butyl-trans-cinnamic acid (1.3 g, 6.4 mmol, EMKA-Chemie) andethyl 6-amino-2H,3H,4H-benzo[e]1,4-oxazaperhydroine-2-carboxylate,Example 13(b), (1.4 g, 6.4 mmol) provided, after purification by silicagel chromatography (85:15 CH₂Cl₂:EtOAc), the title product as a paleyellow solid. MP 207-208° C. MS (ESI, pos. ion) m/z: 409 (M+1).

EXAMPLE 14

(2E)-3-[4-(tert-Butyl)phenyl]-N-[2-(hydroxymethyl)(2H,3H,4H-benzo[3,4-e]1,4-oxazaperhydroin-6-yl)]prop-2-enamide

A solution of ethyl6-{(2E)-3-[4-(tert-butyl)phenyl]prop-2-enoylamino}-2H,3H,4H-benzo[e]1,4-oxazaperhydroine-2-carboxylate,Example 13, (410 mg, 1.0 mmol) in THF (5 mL, Aldrich), magneticallystirred in a round-bottomed flask under N₂ at 0° C., was treated withlithium borohydride (1.5 mL, 3.0 mmol, 2.0 M in THF, Aldrich). Thereaction mixture was allowed to warm to 25° C., and stirred at thattemperature for 3 h. The reaction was quenched by the addition of satdNH₄Cl (5 mL), stirred for 30 min at 25° C. and extracted with EtOAc(2×15 mL). The combined organic extract was washed with satd NaCl, driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by silicagel chromatography (1:1 CH₂Cl₂:EtOAc) provided the title product as apale yellow solid. MP 165-167° C. MS (ESI, pos. ion) m/z: 367 (M+1).

EXAMPLE 15

(2E)-N-[(3S)-3-(Hydroxymethyl)(2H,3H-benzo[e]1,4-dioxan-6-yl)]-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) 2-[((2R)Oxiran-2-yl)methoxy]-5-nitrobenzaldehyde. A mixture of(R)-glycidyl tosylate (1.1 g, 5 mmol, Aldrich),2-hydroxy-5-nitrobenzaldehyde (840 mg, 5.0 mmol, Aldrich) and solidK₂CO₃ (1.4 g, 10 mmol) in DMF (5 mL, Aldrich) was magnetically stirredin a round-bottomed flask at 100° C. under N₂ for 30 min. The reactionmixture was allowed to cool to 25° C., water (20 mL) was added, and themixture was extracted with EtOAc (3×30 mL). The combined extracts werewashed with water (2×20 mL), satd NaCl (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (4:1 hexane:EtOAc) provided the title product. MS (ESI,pos. ion) m/z: 224 (M+1).

(b) ((2S)-7-Nitro-2H,3H-benzo[e]1,4-dioxan-2-yl)methan-1-ol. To asolution 2 0 of 2-[((2R)oxiran-2-yl)methoxy]-5-nitrobenzaldehyde,Example 15(a), (670 mg, 3.0 mmol) in CH₂Cl₂ (10 mL), magneticallystirred in a round-bottomed flask at 0° C., was added 86%m-chloroperbenzoic acid (350 mg, 2.0 mmol, Aldrich). The reactionmixture was allowed to warm to 25° C. and stirred at that temperaturefor 18 h. The mixture was then diluted with CH₂Cl₂ (20 mL), washed with10% Na₂S₂O₃ (3 mL), NaHCO₃ (3×5 mL), satd NaCl (3 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The resulting residue wastreated with MeOH (20 mL) and 1 N NaOH (6 mL) and stirred at 25° C. for16 h. The reaction mixture was diluted with water (10 mL) and extractedwith EtOAc (3×10 mL). The combined organic extracts were washed withsatd NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (3:2 hexane:EtOAc) providedthe product. MS (ESI, pos. ion) m/z: 212 (M+1).

(c)(2E)-N-[(3S)-3-(Hydroxymethyl)(2H,3H-benzo[e]1,4-dioxan-6-yl)]-3-[4-(tert-butyl)phenyl]prop-2-enamide.A mixture of ((2S)-7-nitro-2H,3H-benzo[e]1,4-dioxan-2-yl)methan-1-ol,Example 15(b), (110 mg, 0.5 mmol) and 10% Pd on carbon (20 mg, Aldrich)in MeOH (5 mL), in a round-bottomed flask, was magnetically stirredunder 1 atm H₂ for 2 h. The mixture was purged with N₂, filtered througha pad of Celite and concentrated in vacuo to provide the crude aniline[MS (ESI, pos. ion) m/z: 182 (M+1)]. Analogous to the procedure used toprepare Example 1, 4-tert-butyl-trans-cinnamic acid (102 mg, 0.5 mmol,EMKA Chemie) and the crude aniline, provided the title product as awhite solid. MP 169-171° C. MS (ESI, pos. ion) m/z: 368 (M+1).

EXAMPLE 16

(2E)-N-[(3R)-3-(Hydroxymethyl)(2H,3H-benzo[e]1,4-dioxan-6-yl)]-3-[4-(tert-butyl)phenyl]prop-2-enamide

Analogous to the procedure described for Example 15, the title productwas prepared starting from (S)-glycidyl tosylate (Aldrich),2-hydroxy-5-nitrobenzaldehyde (Aldrich) and 4-tert-butyl-trans-cinnamicacid (EMKA Chemie). MP 170-171° C. MS (ESI, pos. ion) m/z: 368 (M+1).

EXAMPLE 17

(2E)-N-[(2R)-2-(Hydroxymethyl)(2H,3H-benzo[3,4-e]1,4-dioxan-6-yl)]-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) (2-Methoxy-4-nitrophenyl)methan-1-ol. To a solution of2-methoxy-4-nitrobenzoic acid (2.0 g, 10 mmol, Aldrich) in THF (30 mL),magnetically stirred at 0° C. under N₂ in a round-bottomed flaskequipped with a reflux condenser, was added borane-THF complex (30 mL,30 mmol, 1.0 M in THF, Aldrich). The reaction mixture was stirred atreflux overnight. The reaction was quenched by the careful addition ofMeOH (5 mL), followed by 1 N NaOH (30 mL). The mixture was extractedwith EtOAc (2×50 mL), the combined organic extracts were washed withsatd NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo to givethe product. MS (ESI, neg. ion) m/z: 182 (M−1).

(b) 2-Methoxy-4-nitrobenzaldehyde. A mixture of(2-methoxy-4-nitrophenyl)methan-1-ol, Example 17(a), (1.6 g, 8.9 mmol)and MnO₂ (15 g, 180 mmol, Aldrich) in 1:1 hexane: CH₂Cl₂ (60 mL) wasmagnetically stirred at 40° C. for 3 h. The solid was removed byfiltration and washed with CH₂Cl₂. The filtrate was concentrated invacuo and the residue was recrystallized from EtOAc and hexane to givethe title product. MS (ESI, neg. ion) m/z: 180 (M−1).

(c) 2-Hydroxy-4-nitrobenzaldehyde. To a solution of2-methoxy-4-nitrobenzaldehyde, Example 17(b), (190 mg, 1.0 mmol) inCH₂Cl₂ (5 mL), magnetically stirred at −78° C. in a round-bottomedflask, was added BBr₃ (0.19 mL, 2.0 mmol, Aldrich). The reaction mixturewas allowed to warm to 25° C. and stirred at that temperature for 2 h.The reaction mixture was then cooled to −78° C., and treated with MeOH(5 mL). The mixture was allowed to warm to 25° C. , stirred at thattemperature for 30 min, then concentrated in vacuo. Purification bysilica gel chromatography (3:2 hexane:EtOAc) provided2-hydroxy-4-nitrobenzaldehyde. MS (ESI, neg. ion) m/z: 166 (M−1).

(d)(2E)-N-[(2R)-2-(Hydroxymethyl)(2H,3H-benzo[3,4-e]1,4-dioxan-6-yl)]-3-[4-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure described for Example 15, the title productwas obtained as a white solid from 2-hydroxy-4-nitrobenzaldehyde,Example 17(c), (S)-glycidyl tosylate (Aldrich) and4-tert-butyl-trans-cinnamic acid (EMKA-Chemie). MP 159-160° C. MS (ESI,pos. ion) m/z: 368 (M+1).

EXAMPLE 18

(2E)-N-[(2S)-2-(Hydroxymethyl)(2H,3H-benzo[3,4-e]1,4-dioxan-6-yl)]-3-[4-(tert-butyl)phenyl]prop-2-enamide

Analogous to the procedure described for Example 15, the title productwas prepared starting from 2-hydroxy-4-nitrobenzaldehyde, Example 17(c),(R)-glycidyl tosylate (Aldrich) and 4-tert-butyl-trans-cinnamic acid(EMKA Chemie). MP 169-170° C. MS (ESI, pos. ion) m/z: 368 (M+1).

EXAMPLE 19

(2E)-3-[4-(tert-Butyl)phenyl]-N-(7-1,2,3,4-tetrahydroquinolyl)prop-2-enamide

(a) 7-Nitro-1,2,3,4-tetrahydroquinoline. To a round-bottomed flaskequipped with magnetic stirring was added 1,2,3,4-tetrahydroquinoline(6.3 mL, 50 mmol, Aldrich) and 96% H₂SO₄ (42 mL). The mixture wasstirred until all of the amine had dissolved, then cooled to 0° C. andtreated with KNO₃ (5.9 g, 59 mmol) in portions. The reaction mixture wasallowed to warm to 25° C. and stirred overnight at that temperature. Themixture was then cooled to 0° C. and neutralized with solid NaOHfollowed by 5 N NaOH until pH 11 was reached. The mixture was extractedwith CH₂Cl₂ and the extract was dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (8:1hexane:EtOAc) provided 7-nitro-1,2,3,4-tetrahydroquinoline as an orangesolid. MS (ESI, pos. ion) m/z 179 (M+1).

(b) 7-1,2,3,4-Tetrahydroquinolylamine. Analogous to the procedure usedto prepare Example 3(a), 7-nitro-1,2,3,4-tetrahydroquinoline, Example19(a), (0.35 g, 2.0 mmol) provided the aniline as a pale gray oil. MS(ESI, pos. ion) m/z: 149 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(7-1,2,3,4-tetrahydroquinolyl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,7-1,2,3,4-tetrahydroquinolyl, Example 19(b), (280 mg, 1.9 mmol) and4-tert-butyl-trans-cinnamic acid (0.33 g, 1.6 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (3:1hexane:EtOAc) then recrystallization from EtOAc and hexane, the titleproduct as a yellow solid. MP 225-227° C. MS (ESI, pos. ion) m/z: 335(M+1).

EXAMPLE 20

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methyl(7-1,2,3,4-tetrahydroquinolyl))-prop-2-enamide

(a) 1-methyl-7-nitro-1,2,3,4-tetrahydroquinoline. To a solution of7-nitro-1,2,3,4-tetrahydro-quinoline, Example 19(a), (0.36 g, 2 mmol) inDMF (10 mL), magnetically stirred under N₂ at 0° C. in a 15 mLround-bottomed flask, was added sodium hydride (0.12 g, 3 mmol, 60%dispersion in mineral oil, Aldrich). After stirring for 10 min, thereaction mixture was treated with iodomethane (0.24 mL, 4 mmol, Aldrich)dropwise. The reaction mixture was stirred at 0° C. for 1 h, at 25° C.for an additional 1 h, then partitioned between EtOAc and satd NaCl. Theaqueous layer was extracted with EtOAc (40 mL) and the combined organicextract was dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (7:1 hexane:EtOAc) providedthe product as an orange oil. MS (ESI, pos. ion) m/z: 193 (M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methyl(7-1,2,3,4-tetrahydroquinolyl))-prop-2-enamide.Analogous to the procedure described for Example 19, steps (b)-(c),1-methyl-7-nitro-1,2,3,4-tetrahydroquinoline, Example 20(a), (240 mg,1.3 mmol) and 4-tert-butyl-trans-cinnamic acid (0.23 g, 1.1 mmol,EMKA-Chemie) provided, after purification by silica gel chromatography(4:1 hexane:EtOAc) then recrystallization from EtOAc and hexane, thetitle product as a yellow solid. MP 200-202° C. MS (ESI, pos. ion) m/z:349 (M+1).

EXAMPLE 21

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(6-1,3,4-trihydroquinolyl))prop-2-enamide

(a) 6-Nitro-1,3,4-trihydroquinolin-2-one. To a round-bottomed flaskequipped with magnetic stirring was added 3,4-dihydro-2(1H)-quinolinone(1.47 g, 10 mmol, Aldrich) and 96% H₂SO₄ (8.3 mL). The mixture wasstirred until all of the material was dissolved, then cooled to 0° C.and treated with KNO₃ (1.2 g, 11.7 mmol) in portions. The reactionmixture was allowed to warm to 25° C. and stirred at that temperatureovernight. The mixture was basified to pH 9 with 35% NaOH, resulting ina precipitate. The solid was collected by filtration, washed with waterand dried in vacuo at 50° C. to provide the title product as a yellowsolid. MS (ESI, pos. ion) m/z: 193 (M+1).

(b) 6-Amino-1,3,4-trihydroquinolin-2-one. Analogous to the procedureused to prepare Example 3(a), 6-nitro-1,3,4-trihydroquinolin-2-one,Example 21(a), (1.7 g, 8.9 mmol) was converted to the title product as atan solid. MS (ESI, pos. ion) m/z: 163 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(6-1,3,4-trihydroquinolyl))prop-2-enamide.Analogous to the procedure used to prepare Example 1,6-amino-1,3,4-trihydroquinolin-2-one, Example 21(b), (0.68 g, 4.2 mmol)and 4-tert-butyl-trans-cinnamic acid (0.86 g, 4.2 mmol, EMKA-Chemie)provided, after recrystallization from MeOH, the title product as a paleyellow solid. MP 275-276° C. MS (ESI, pos. ion) m/z: 349 (M+1).

EXAMPLE 22

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(7-1,3,4-trihydroquinolyl))prop-2-enamide

(a) Ethyl 3-(2,4-dinitrophenyl)prop-2-enoate. A suspension of sodiumhydride (2.0 g, 50 mmol, 60% dispersion in mineral oil, Aldrich) inanhydrous THF (100 mL) was magnetically stirred under N₂ at 25° C. andtreated dropwise with triethyl phosphonoacetate (10 mL, 11 g, 51 mmol,Aldrich). The reaction mixture was stirred for 1 h at 25° C. thentreated with 2,4-dinitrobenzaldehyde (9.0 g, 46 mmol, Aldrich) inportions. After stirring overnight at 25° C., the reaction was quenchedby the addition of water (50 mL) and concentrated in vacuo to remove theTHF. The remaining aqueous mixture was extracted with EtOAc (2×150 mL).The combined organic extract was washed with water (4×100 mL), satd NaCl(75 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (1:4 hexane:EtOAc) providedthe title product as a dark oil.

(b) 7-Amino-1,3,4-trihydroquinolin-2-one. Ethyl3-(2,4-dinitrophenyl)prop-2-enoate, Example 22(a), (3.0 g, 11 mmol) wasdissolved in glacial acetic acid (240 mL), treated with 10% Pd on carbon(2.4 g, Aldrich) and hydrogenated on a Parr shaker apparatus at 65° C.,under 60 psi H₂, for 3 h. The reaction mixture was allowed to cool to25° C., purged with N₂, filtered through Celite and the filtercakewashed with acetic acid (200 mL) and EtOH (200 mL). The combinedfiltrate was concentrated in vacuo, then treated with 1 N NaOH (150 mL)and extracted with EtOAc (3×100 mL). The combined organic extract waswashed with satd NaCl (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (EtOAc)provided the title product as a pale yellow solid. MS (ESI, pos. ion)m/z: 163 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(7-1,3,4-trihydroquinolyl))prop-2-enamide.Analogous to the procedure used to prepare Example 1,7-amino-1,3,4-trihydroquinolin-2-one, Example 22(b), (300 mg, 1.8 mmol)and 4-tert-butyl-trans-cinnamic acid (370 mg, 1.8 mmol, EMKA-Chemie)provided the title product as white crystals. MP 288-290° C. MS (ESI,pos. ion) m/z: 349 (M+1).

EXAMPLE 23

(2E)-3-[4-(tert-Butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide

To a round-bottomed flask equipped with magnetic stirring was added4-tert-butyl-trans-cinnamic acid (530 mg, 2.43 mmol, EMKA-Chemie),CH₂Cl₂ (10 mL), and DMF (10 uL, Aldrich) under N₂. The solution wastreated dropwise with oxalyl chloride (3.0 mL, 6.0 mmol, 2.0 M inCH₂Cl₂, Aldrich) then stirred at 25° C. for 1 h. The reaction mixturewas concentrated in vacuo and treated with 3-aminophenol (265 mg, 2.43mmol, Aldrich), THF (20 mL) and satd K₂CO₃ (15 mL). The reaction mixturewas stirred at 25° C. overnight, then acidified to pH˜4.5 with 1 N HCl.The mixture was extracted with EtOAc (2×30 mL), the combined organicextract was dried and concentrated in vacuo. Purification by silica gelchromatography (2:1 hexane:EtOAc) provided the title product as an oil.MS (ESI, pos. ion) m/z: 296 (M+1).

EXAMPLE 24

2-(3-{(2E)-3-[4-(tert-Butyl)phenyl]prop-2-enoylamino}phenoxy)acetic acid

To a round-bottomed flask equipped with magnetic stirring was added(2E)-3-[4-(tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, Example23, (120 mg, 0.407 mmol), THF (10 mL), tert-butyl bromoacetate (60 uL,0.407 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture wasstirred at 25° C. overnight. The mixture was extracted with EtOAc (20mL), the organic extract washed with water (20 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting residue was treatedwith trifluoroacetic acid (10 mL), stirred at 25° C. for 2 h, thenconcentrated in vacuo. Purification by silica gel chromatography (1:2hexane:EtOAc) provided the title product as an off-white solid. MP166-172° C. MS (ESI, pos. ion) m/z: 354 (M+1).

EXAMPLE 25

(2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(2-hydroxyethoxy)phenyl]prop-2-enamide

To a round-bottomed flask, equipped with magnetic stirring and refluxcondenser, was added(2E)-3-[4-(tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, Example23, (200 mg, 0.68 mmol), THF (10 mL), 2-bromoethanol (200 uL, 2.80 mmol,Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred atreflux for 5 h. After allowing to cool to 25° C., the mixture wasextracted with EtOAc (20 mL). The organic extract was washed with water(20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (2:1 hexane:EtOAc) providedthe title product as a colorless oil. MS (ESI, pos. ion) m/z: 340 (M+1).

EXAMPLE 26

(2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(2-methoxyethoxy)phenyl]prop-2-enamide

(a) 3-(2-Methoxyethoxy)phenylamine. To a round-bottomed flask equippedwith magnetic stirring was added 3-aminophenol (1.2 g, 11 mmol,Aldrich), TBF (15 mL) and sodium hydride (440 mg, 11 mmol, 60% inmineral oil, Aldrich) at 0° C. The reaction mixture was allowed to stirat 0° C. for 30 min, then 2-bromoethyl methyl ether (1.0 mL, 11 mmol,Aldrich) was added dropwise. The reaction mixture was stirred at 25° C.overnight, then cooled to 0° C. and quenched with satd NaCl (10 mL). Themixture was extracted with EtOAc (20 mL) and the organic phase waswashed with water (20 mL), dried over Na₂SO₄, filtered and concentratedin vacuo to provide the title product. MS (ESI, pos. ion) m/z: 168(M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(2-methoxyethoxy)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 2,3-(2-methoxyethoxy)phenylamine, Example 26(a), (350 mg, 2.45 mmol) and4-tert-butyl-trans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (5:1hexane:EtOAc), the title product as a colorless oil. MS (ESI, pos. ion)m/z: 354 (M+1).

EXAMPLE 27

(2E)-3-[4-(tert-Butyl)phenyl]-N-{3-[2-(1,3-dioxobenzo[c]azolin-2-yl)ethoxy]phenyl}prop-2-enamide

(a) 2-[2-(3-Nitrophenoxy)ethyl]benzo[c]azoline-1,3-dione. To around-bottomed flask, equipped with magnetic stirring, an additionfunnel and a reflux condenser, was added 3-nitrophenol (2.0 g, 14 mmol,Fluka), triphenylphosphine (4.9 g, 19 mmol, Aldrich) and DMF (20 mL). Asolution of N-[2-hydroxyethyl]phthalimide (2.7 mg, 14 mmol, Aldrich) anddiethyl azodicarboxylate (3.3 g, 19 mmol, Aldrich) in DMF (20 mL) wasadded dropwise through the addition funnel at 25° C. The reactionmixture was stirred at 60° C. for 12 h. The reaction mixture wasconcentrated in vacuo, dissolved in EtOAc (55 mL), and washed with satdNaCl (20 mL) and water (20 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (2:1 hexane:EtOAc) provided the title product. MS (ESI,pos. ion) m/z: 313 (M+1).

(b) 2-[2-(3-Aminophenoxy)ethyl]benzo[c]azoline-1,3-dione. In around-bottomed flask, equipped with magnetic stirring, a solution of2-[2-(3-nitrophenoxy)ethyl]benzo[c]azoline-1,3-dione, Example 27(a),(1.9 g, 6.1 mmol) in 0.5% acetic acid in EtOAc (10 mL), under N₂, wastreated with 10% Pd on carbon (500 mg, Aldrich). The suspension waspurged with H₂ and stirred under 1 atm H₂ at 25° C. overnight. Thesuspension was purged with N₂ and filtered through a pad of Celite. Thesolvent was removed in vacuo to provide the title product.

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-{3-[2-(1,3-dioxobenzo[c]azolin-2-yl)ethoxy]phenyl}prop-2-enamide.Analogous to the procedure used to prepare Example 2,2-[2-(3-aminophenoxy)ethyl]benzo[c]azoline-1,3-dione, Example 27(b),(1.7 g, 6.1 mmol) and 4-tert-butyl-trans-cinnamic acid (1.2 g, 6.0 mmol,EMKA-Chemie) provided, after purification by silica gel chromatography(3:1 hexane:EtOAc), the title product as an off-white film. MS (ESI,pos. ion) m/z: 469 (M+1).

EXAMPLE 28

(2E)-N-[3-(2-Aminoethoxy)phenyl]-3-[4-(tert-butyl)phenyl]prop-2-enamide

To a round-bottomed flask equipped with magnetic stirring was addedExample 27,(2E)-3-[4-(tert-butyl)phenyl]-N-{3-[2-(1,3-dioxobenzo[c]azolin-2-yl)ethoxy]phenyl}prop-2-enamide,(856 mg, 1.83 mmol), EtOH (15 mL) and hydrazine (574 uL, 18.3 mmol,Aldrich). The reaction mixture was stirred at 25° C. for 2 h. Themixture was concentrated in vacuo, the residue dissolved in EtOAc (40mL), washed with 10% K₂CO₃ (15 mL), water (15 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (step gradient, EtOAc followed by 1:1 EtOAc:EtOH)provided the title product as an oil. MS (ESI, pos. ion) m/z: 339 (M+1).

EXAMPLE 29

(2E)-3-[4-(tert-Butyl)phenyl]-N-indolin-6-ylprop-2-enamide

(a) tert-Butyl 6-(1-aza-2,2-diphenylvinyl)indolinecarboxylate. To asolution of benzophenone imine (0.91 g, 5.0 mmol, Aldrich) in CH₂Cl₂ (35mL), magnetically stirred at 25° C. in a round-bottomed flask, was addeda solution of 6-aminoindoline dihydrochloride (1.04 g, 5.0 mmol,Biosynth AG) in CH₂Cl₂ (40 mL). The reaction mixture was stirred at 25°C. for 12 h, then diluted with CH₂Cl₂ (30 mL), washed with water (30mL), satd NaCl (30 mL), dried over MgSO₄, filtered and concentrated invacuo. The crude product [MS (ESI, pos. ion) m/z: 299 (M+1)] wasdissolved in 1,4-dioxane and treated with di-tert-butyl dicarbonate (8.0mL, 8.0 mmol, 1.0 M in THF, Aldrich) and 5 N aq. Na₂CO₃ (5 mL). Thereaction mixture was magnetically stirred at 25° C. until complete, thendiluted with water (30 mL), and extracted with EtOAc (3×30 mL). Thecombined organic extract was washed with satd NaCl (30 mL), dried overMgSO₄, filtered and concentrated in vacuo. Purification by silica gelchromatography (4:1 hexane EtOAc) provided the title product. MS (ESI,pos. ion) m/z: 399 (M+1).

(b) tert-Butyl 6-aminoindolinecarboxylate. In a round-bottomed flask, asolution of tert-butyl 6-(1-aza-2,2-diphenylvinyl)indolinecarboxylate,Example 29(a), (0.80 g, 2.0 mmol) in 1,4-dioxane (10 mL) was treatedwith 1 N aq. HCl (10 mL). The reaction mixture was magnetically stirredovernight at 25° C., then diluted with water (20 mL) and extracted withethyl ether (30 mL). The aqueous phase was treated with 5 N NaOH (10 mL)and extracted with ethyl ether (3×30 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography (3:2 hexane EtOAc) provided the titleproduct. MS (ESI, pos. ion) m/z: 235 (M+1).

(c) (2E)-3-[4-(tert-Butyl)phenyl]-N-indolin-6-ylprop-2-enamide.Analogous to the procedure used to prepare Example 1, tert-butyl6-aminoindoline-carboxylate, Example 29(b), (230 mg, 1.0 mmol) and4-tert-butyl cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided,after purification by silica gel chromatography (7:3 hexane EtOAc), acrude product which was dissolved in CH₂Cl₂ (5 mL) and treated with 4 NHCl in dioxane (5 mL, Aldrich). The reaction mixture was magneticallystirred at 25° C. for 1 h, then washed with 5 N NaOH (15 mL), satd NaCl(15 mL), dried over MgSO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (55:45 hexane EtOAc) providedthe title product. MP 153-167° C. MS (ESI, pos. ion) m/z: 321 (M+1).

EXAMPLE 30

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-6-yl)prop-2-enamide

(a) 1-Methylindoline-6-ylamine. To a round-bottomed flask was added6-nitroindoline (1.64 g, 10.0 mmol, Aldrich), 37% aq. formaldehyde (2.35g, 30.0 mmol, Aldrich) and THF (40 mL). The reaction mixture wasmagnetically stirred at 25° C. and treated with sodium cyanoborohydride(1.89 g, 30.0 mmol, Aldrich). The reaction mixture was allowed to stirat 25° C. for 30 min, then washed with satd Na₂CO₃. The aqueous phasewas extracted with ethyl ether, the organic phases combined andconcentrated in vacuo to a residue. Analogous to the procedure ofGoswami, P.; Chowdhury, P.; Indian J Chem, Sect B, 1997, 36 (2),185-186, the crude residue was dissolved in tetrahydrofuran (60 mL) andadded to Zn dust (0.43 g, 6.6 mmol, Aldrich) and AlCl₃.6H₂O (9.6 g, 40mmol, Aldrich) in water (2 mL), magnetically stirred at 25° C. Thereaction mixture was stirred at 25° C. for 16 h, then filtered. Thefiltrate was added to cold water (300 mL) and extracted with CH₂Cl₂(3×100 mL). The combined organic extract was concentrated in vacuo toprovide the title product as a brown solid. MS (ESI, pos. ion) m/z: 149(M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-6-yl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,1-methylindoline-6-ylamine, Example 30(a), (150 mg, 1.0 mmol) and4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie)provided the title product as an amorphous yellow solid. MS (ESI, pos.ion) m/z: 335 (M+1).

EXAMPLE 31

(2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) N-(2-Bromo-5-nitrophenyl)acetamide. A solution of2-bromo-5-nitroaniline (43 g, 0.20 mol, Aldrich) in glacial acetic acid(1.3 L), magnetically stirred at 25° C., was treated with aceticanhydride (20 mL, 0.21 mol). The reaction mixture was allowed to stir at25° C. overnight, then quenched by pouring into water (6 L). Theprecipitate was collected by filtration, washed with water, and dried invacuo to provide the title product as an off white solid. MS (ESI, pos.ion) m/z: 259, 262 (M+1, M+3).

(b) N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide. To aflame-dried round-bottomed flask, equipped with magnetic stirring and anaddition funnel, was added N-(2-bromo-5-nitrophenyl)acetamide, Example31(a), (48 g, 0.19 mol), solid potassium carbonate (103 g, 744 mmol) andanhydrous DMF (830 mL). The resulting solution was stirred at 25° C. andtreated dropwise, through the addition funnel, with a solution of3-bromo-2-methylpropene (38 mL, 380 mmol, Aldrich) in anhydrous DMF (100mL) over 45 min. The reaction mixture was stirred at 25° C. overnight,then filtered and treated with satd NaHCO₃. The organic layer wasremoved and the aqueous layer was extracted with EtOAc (3×150 mL). Thecombined organic extracts were washed with water (4×70 mL), satd NaCl(70 mL), dried over MgSO₄, filtered and concentrated in vacuo to providethe title product as a golden solid. MS (ESI, pos. ion) m/z: 313, 315(M+1, M+3).

(c). 1-Acetyl-3,3-dimethyl-6-nitroindoline. To a flame-driedround-bottomed flask, equipped with magnetic stirring, was addedN-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide, Example31(b), (55 g, 0.18 mol), tetraethylammonium chloride hydrate (30.8 g,186 mmol, Aldrich), sodium formate (14.4 g, 212 mmol, Aldrich), sodiumacetate (36.3 g, 443 mmol) and anhydrous DMF (443 mL). The resultingsolution was purged with N₂ and treated with palladium (II) acetate(3.97 g, 17.7 mmol, Aldrich). The reaction mixture was stirred in an oilbath at 80° C. for 15 h, then allowed to cool to 25° C. and filteredthrough a pad of Celite. The Celite was washed with EtOAc and thecombined filtrate was washed with satd NaHCO₃ (500 mL). The aqueouslayer was extracted with EtOAc (3×100 mL) and the combined organicextract was washed with water (4×100 mL), satd NaCl (2×100 mL), driedover MgSO₄, filtered and concentrated in vacuo to provide1-acetyl-3,3-dimethyl-6-nitroindoline as a brown solid. MS (ESI, pos.ion) m/z: 235 (M+1).

(d)(2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyl)phenyl)prop-2-enamide.To a solution of 1-acetyl-3,3-dimethyl-6-nitroindoline, Example 31(c),(110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in around-bottomed flask at 0° C., was added tin (II) chloride dihydrate(0.67 g, 2.96 mmol, Aldrich) and cond HCl (0.3 mL). The reaction mixturewas stirred at 0° C. for 10 min, allowed to warm to 25° C. then stirredat that temperature overnight. The reaction mixture was washed with 10 NNaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogousto the procedure used to prepare Example 1, the crude product and4-tert-butyl-trans-cinnamic acid (92 mg, 0.45 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (2:3hexane:EtOAc), the title product. MP 121° C. MS (ESI, pos. ion) m/z: 391(M+1).

EXAMPLE 32

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1,3,3-trimethylindolin-6-yl)prop-2-enamide

(a) 3,3-Dimethyl-6-nitroindoline. To a round-bottomed flask, equippedwith magnetic stirring and a reflux condenser, was added1-acetyl-3,3-dimethyl-6-nitroindoline, Example 31(c), (1.73 g, 7.39mmol) and EtOH (20 mL). The solution was treated with 12 N HCl (20 mL)then stirred and heated at reflux for 2 h. The reaction mixture wascooled to 0° C., providing a precipitate which was collected byfiltration and dried in vacuo to afford the title product as anoff-white solid. MS (ESI, pos. ion) m/z: 193 (M+1).

(b) 1,3,3-Trimethylindoline-6-ylamine. A solution of3,3-dimethyl-6-nitroindoline, Example 32(a), (0.23 g, 1.2 mmol) inanhydrous DMF (15 mL) was magnetically stirred at 25° C. and treatedwith sodium hydride (0.14 g, 3.6 mmol, 60% dispersion in mineral oil,Aldrich), followed by iodomethane (0.17, 1.3 mmol, Aldrich). Thereaction mixture was stirred at 25° C. for 3 h, then quenched with water(40 mL) and extracted with EtOAc (3×30 mL). The combined extract wasconcentrated in vacuo to provide a residue [MS (ESI, pos. ion) m/z: 207(M+1)] which was immediately dissolved in ethyl ether (5 mL),magnetically stirred at 0° C., and treated with tin (II) chloridedihydrate (1.7 g, 7.5 mmol, Aldrich) and cond HCl (0.8 mL). The reactionmixture was stirred at 0° C. for 10 min, allowed to warm to 25° C., thenstirred at that temperature overnight. The reaction mixture was washedwith 10 N NaOH (20 mL) and extracted with EtOAc (3×50 mL). The combinedextracts were concentrated in vacuo and purified by silica gelchromatography to provide the title product. MS (ESI, pos. ion) m/z: 177(M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(1,3,3-trimethylindolin-6-yl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,1,3,3-trimethylindoline-6-ylamine, Example 32(b), (176 mg, 1.0 mmol) and4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (3:2hexane:EtOAc), the title product. MP 90-101° C. MS (ESI, pos. ion) m/z:363 (M+1).

EXAMPLE 33

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-6-yl)prop-2-enamide

(a) 1-Methylindole-6-ylamine. To a round-bottomed flask was added6-nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). Thesolution was stirred magnetically and treated with sodium hydride (0.40g, 10 mmol, 60% dispersion in mineral oil, Aldrich) followed byiodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25° C.for 30 min, then the reaction mixture was quenched by the addition ofwater (75 mL) and extracted with EtOAc. The organic extract wasconcentrated in vacuo to provide a residue which was dissolved in EtOH(40 mL), treated with 10% Pd on carbon (400 mg, Aldrich), purged with H₂and magnetically stirred under 1 atm H₂ for 4 h. The suspension waspurged with N₂, filtered through a pad of Celite and concentrated invacuo. Purification by silica gel chromatography (50:50 hexane:EtOAc)provided the aniline. MS (ESI, pos. ion) m/z: 147 (M+1).

(b) (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-6-yl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,1-methylindole-6-ylamine, Example 33(a), (150 mg, 1.0 mmol) and4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol), after purificationby silica gel chromatography (65:35 hexane:EtOAc), provided the titleproduct as a yellow solid. MP 95° C. MS (ESI, pos. ion) m/z: 333 (M+1).

EXAMPLE 34

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-5-yl)prop-2-enamide

(a) 1-Methylindole-5-ylamine. To a round-bottomed flask was added5-nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). Thesolution was stirred magnetically and treated with sodium hydride (0.40g, 10 mmol, 60% dispersion in mineral oil, Aldrich) followed byiodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25° C.for 30 min, then the reaction mixture was quenched by the addition ofwater (75 mL) and extracted with EtOAc. The organic extract wasconcentrated in vacuo to provide a crude residue. Analogous to theprocedure of Goswami, P.; Chowdhury, P.; Indian J Chem, Sect B, 1997, 36(2), 185-186, the crude residue was dissolved in THF (40 mL) and addedto Zn dust (0.22 g, 3.3 mmol, Aldrich) and AlCl₃.6H₂O (4.78 g, 19.8mmol, Aldrich) in water (1 mL), magnetically stirred at 25° C. Thereaction mixture was stirred at 25° C. for 16 h, then filtered. Thefiltrate was added to cold water (300 mL) and extracted with CH₂Cl₂(3×100 mL). The combined organic extract was concentrated in vacuo toprovide the title product. MS (ESI, pos. ion) m/z: 147 (M+1).

(b) (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-5-yl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,1-methylindole-5-ylamine, Example 34(a), (150 mg, 1.0 mmol) and4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (65:35hexane:EtOAc), the title product as a crystalline yellow solid. MP 171°C. MS (ESI, pos. ion) m/z: 333 (M+1).

EXAMPLE 35

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-5-yl)prop-2-enamide

(a) 1-Methyl-5-nitroindoline. To a round-bottomed flask equipped withmagnetic stirring was added 5-nitroindoline (0.82, 5.0 mmol, Aldrich),iodomethane (0.71 g, 5.0 mmol, Aldrich), sodium hydroxide (0.24, 6 mmol)and DMF (20 mL). The reaction mixture was stirred at 25° C. for 3 h,diluted with water (50 mL), extracted with EtOAc (3×40 mL) and thecombined extracts were concentrated in vacuo. Purification by silica gelchromatography 97:3 hexane:EtOAc) provided the title product. MS (ESI,pos. ion) m/z: 179 (M+1).

(b) 1-Methylindoline-5-ylamine. To a solution of1-methyl-5-nitroindoline, Example 35(a), (0.55 g, 3.1 mmol) in ethylether (20 mL), magnetically stirred in a round-bottomed flask at 0° C.,was added tin (II) chloride dihydrate (4.5 g, 20 mmol, Aldrich) and condHCl (2.5 mL). The reaction mixture was stirred at 0° C. for 10 min,allowed to warm to 25° C. then stirred at that temperature overnight.The reaction mixture was washed with 10N NaOH (30 mL) and the aqueousphase extracted with EtOAc (3×20 mL). The combined organic extracts wereconcentrated in vacuo. Purification by silica gel chromatography (55:45hexane:EtOAc) provided the aniline. MS (ESI, pos. ion) m/z: 149 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-5-yl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,1-methylindoline-5-ylamine, Example 35(b), (150, 1.0 mmol) and4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (60:40hexane:EtOAc), the title product as a crystalline yellow solid. MP 194°C. MS (ESI, pos. ion) m/z: 335 (M+1).

EXAMPLE 36

(2E)-N-Benzoxazol-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) 5-Nitrobenzoxazole. Following the procedure of A. R. Katritzky etal. Heterocycles 1995, 41, 345, to a round-bottomed flask was added2-amino-4-nitrophenol (5.0 g, 32 mmol, Aldrich), trimethyl orthoformate(20 mL, 180 mmol, Aldrich) and p-toluenesulfonic acid monohydrate (300mg, 1.6 mmol, Aldrich). The reaction mixture was magnetically stirred ina 95° C. oil bath for 1 h, and then allowed to cool to 25° C. Themixture was cooled to 0° C. to provide a precipitate which was collectedby filtration, washed with cold toluene, pentane, then dried in vacuo toafford the title product as a dark brown powder.

(b) Benzoxazole-5-ylamine. Analogous to the procedure used to prepareExample 3(a), 5-nitrobenzoxazole, Example 36(a), (2.4 g, 15 mmol)provided, after purification by silica gel chromatography (stepgradient, 7:3 then 4.5:5.5 then 3:7 hexane:EtOAc), the title product. MS(ESI, pos. ion) m/z: 135 (M+1).

(c) (2E)-N-Benzoxazol-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,benzoxazole-5-ylamine, Example 36(b), (530 mg, 4.0 mmol) and4-tert-butyl-trans-cinnamic acid (820 mg, 4.0 mmol, EMKA-Chemie)provided, after twice being purified by silica gel chromatography (7:3hexane:EtOAc then 1.25% MeOH in CH₂Cl₂), the title product as whitecrystals. MP 177° C. MS (ESI, pos. ion) m/z: 321 (M+1).

EXAMPLE 37

(2E)-N-Benzoxazol-6-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) Benzoxazole-6-ylamine. Analogous to the procedure described for thepreparation of Example 36, steps (a)-(b), 2-amino-5-nitrophenol (5.0 g,32 mmol, Aldrich) provided the title product as a pale tan solid. MS(ESI, pos. ion) m/z: 135 (M+1).

(b) (2E)-N-Benzoxazol-6-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,benzoxazole-6-ylamine, Example 37(a), (1.8 g, 13 mmol) and4-tert-butyl-trans-cinnamic acid (2.7 g, 13 mmol, EMKA-Chemie) provided,after purification by silica gel chromatography (6:4:0.2CH₂Cl₂:hexane:MeOH), the title product as a tan solid. MP 147-148° C. MS(ESI, pos. ion) m/z: 321 (M+1).

EXAMPLE 38

(2E)-N-Benzo[b]furan-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) Methyl 2-(2-formyl-4-nitrophenoxy)acetate. To a round-bottomed flaskwas added a suspension of 2-hydroxy-5-nitrobenzaldehyde (10 g, 60 mmol,Aldrich) in anhydrous EtOH (180 mL). The suspension was treated with KOH(4.4 g, 66 mmol) and heated under N₂ with magnetic stirring in a 65° C.oil bath for 45 min. The reaction mixture was allowed to cool to 25° C.and concentrated in vacuo. Anhydrous DMF (180 mL) was added, and thereaction flask was cooled in an ice bath and charged with methylbromoacetate (10 mL, 110 mL, Aldrich). The reaction mixture was stirredfor 3.5 h at 25° C., then the solvent was removed in vacuo. Water (200mL) was added, and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic extract was washed with 1 M H₃PO₄, satd NaHCO₃, andsatd NaCl. After drying over MgSO₄, the organic layer was filtered andconcentrated in vacuo. The residue was recrystallized from CH₂Cl₂ andhexane to afford the title product as a pale yellow solid. MS (ESI, pos.ion) m/z: 240 (M+1).

(b) Ethyl 5-nitrobenzo[d]furan-2-carboxylate. To a 250 mL round-bottomedflask was added methyl 2-(2-formyl-4-nitrophenoxy)acetate, Example38(a), (5.3 g, 22 mmol), EtOH (110 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 g, 24 mmol, Aldrich). Thereaction mixture was magnetically stirred at 25° C. for 20 h, thenconcentrated to approximately half of its volume in vacuo. After coolingthe mixture in an ice bath for 20 min, a precipitate formed which wascollected by filtration and washed with ice cold EtOH. The resultingpale yellow solid was dried in vacuo to provide the title product. MS(ESI, pos. ion) m/z: 253 (M+H₂O).

(c) 5-Nitrobenzo[b]furan-2-carboxylic acid. To a 250 mL round-bottomedflask was added ethyl 5-nitrobenzo[d]furan-2-carboxylate, Example 38(b),(1.0 g, 4.3 mmol), EtOH (10 mL), and KOH (610 mg, 11 mmol) in 10 mL ofH₂O. The reaction mixture was stirred at 25° C. for 24 h, then treatedwith 1 M H₃PO₄ (200 mL) and saturated with solid NaCl. The aqueous layerwas extracted with EtOAc (3×70 mL), and the combined organic extractswere washed with satd NaCl, dried over MgSO₄, filtered and concentratedin vacuo to provide the title product as a yellowish-white powder. MS(ESI, pos. ion) m/z: 225 (M+H₂O).

(d). 5-Nitrobenzofuran. To a 100 mL round-bottomed flask was added5-nitrobenzo[b]furan-2-carboxylic acid, Example 38(c), (860 mg, 4.2mmol), copper (830 mg, 13 mmol, Aldrich), and quinoline (38 mL,Aldrich). The reaction flask was placed in a 185° C. oil bath andmagnetically stirred for 20 min under N₂. After allowing to cool to 25°C., the mixture was filtered through a 1″ pad of Celite. To the filtratewas added 10% aq. HCl (300 mL) and the aqueous layer was extracted withEt₂O (3×100 mL). The combined ethereal layers were washed with 10% HCl(4×200 mL, 1×100 mL), satd NaHCO₃ (200 mL), and satd NaCl (100 mL),dried over MgSO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (10:0.25 hexanes:EtOAc) provided5-nitrobenzofuran as a white solid.

(e) Benzo[b]furan-5-ylamine. To a 150 mL round-bottomed flask was added5-nitrobenzofuran, Example 38(d), (270 mg, 1.7 mmol) and ethyl ether (16mL). The mixture was magnetically stirred at 0° C. under N₂ and treatedwith a solution of tin (II) chloride dihydrate (3.4 g, 15 mmol, Aldrich)in 12 M aq. HCl (2 mL). The reaction mixture was stirred at 0° C. for 10min, then allowed to warm to 25° C. and stirred at that temperature for20 h. Water and 2 N NaOH (pH >10) were added followed by Celite (10 g).The mixture was filtered through a pad of Celite and the filtrateextracted with EtOAc. The organic extract was washed with 2 N NaOH, satdNaCl, dried over K₂CO₃, filtered and concentrated in vacuo to providethe title product as a pale yellow oil. MS (ESI, pos. ion) m/z: 134(M+1).

(f) (2E)-N-Benzo[b]furan-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,benzo[b]furan-5-ylamine, Example 38(e), (230 mg, 1.7 mmol) and4-tert-butyl-trans-cinnamic acid (350 mg, 1.7 mmol, EMKA-Chemie)provided, after purification by silica gel chromatography (9:1hexane:EtOAc), the title product as white crystals. MP 149-150° C. MS(ESI, pos. ion) m/z: 320 (M+1).

EXAMPLE 39

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2,3-dihydrobenzo[b]furan-5-yl)prop-2-enamide

(a) 2,3-Dihydrobenzo[b]furan-5-ylamine. To a 150 mL round-bottomed flaskwas added 5-nitrobenzofuran, Example 38(d), (250 mg, 1.5 mmol), EtOAc(16 mL) and 10% Pd on carbon (33 mg, Aldrich). The suspension wasstirred at 25° C. under 1 atm H₂ for 24 h, then purged with N₂, filteredthrough Celite and concentrated in vacuo to provide the aniline as ared-brown solid. MS (ESI, pos. ion) m/z: 136 (M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-(2,3-dihydrobenzo[b]furan-5-yl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,2,3-dihydrobenzo[b]furan-5-ylamine, Example 39(a), (240 mg, 1.8 mmol)and 4-tert-butyl-trans-cinnamic acid (370 mg, 1.8 mmol, EMKA-Chemie)provided the crude title product. The product was purified by silica gelchromatography (9:1:0.25 hexane:EtOAc:MeOH) to provide 45 mg of thetitle product and additional impure fractions. The impure fractions werecombined and concentrated in vacuo. The residue was dissolved in MeOH(25 mL), treated with 5 N NaOH (10 mL) and stirred for 1 h. The mixturewas diluted with 5 N NaOH (100 mL) and extracted with EtOAc. The organicphase was washed with 5 N NaOH (2×), 5% citric acid, satd NaCl, driedover MgSO₄, filtered and concentrated in vacuo. Purification by silicagel chromatography (8:1:0.5 hexane:EtOAc: 2 M NH3 in MeOH) provided anadditional the title product as a white solid. MP 175-176° C. MS (ESI,pos. ion) m/z: 322 (M+1).

EXAMPLE 40

N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3,3-bis(4-methylphenyl)prop-2-enamide

(a) 3,3-Bis(4-methylphenyl)prop-2-enoic acid. Triethyl phosphonoacetate(2.0 mL, 10 mmol, Aldrich) was added dropwise to a suspension of NaH(0.44 g, 11 mmol, 60% dispersion in mineral oil, Aldrich) in anhydrousTHF (16 mL), magnetically stirred at 0° C. under Ar, in a round-bottomedflask equipped with a reflux condenser. The reaction mixture was allowedto warm to 25° C. then stirred at that temperature for 0.5 h.4,4′-Dimethylbenzophenone (2.1 g, 10 mmol, Aldrich) was added in oneportion and the reaction mixture stirred and heated at reflux for 48 h.After allowing to cool to 25° C., the reaction mixture was quenched withH₂O (30 mL) and extracted with Et₂O (4×10 mL). The combined organicextract was washed with H₂O (5 mL), dried over MgSO₄, filtered andconcentrated in vacuo to an oily residue. The residue was dissolved in1,4-dioxane (2.5 mL), treated with H₂O (7 mL) and KOH (1.1 g, 20 mmol),then stirred and heated at reflux under Ar for 18 h. The reactionmixture was allowed to cool to 25° C., diluted with H₂O (50 mL) andwashed with Et₂O (10 mL). The aqueous phase was acidified with 1 N HCland extracted with chloroform. The combined chloroform extracts werewashed with satd NaCl, dried over MgSO₄, filtered and concentrated invacuo to provide the acid as a white solid. MS (ESI, pos. ion) m/z: 253(M+1).

(b)N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3,3-bis(4-methylphenyl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,3,3-bis(4-methylphenyl)prop-2-enoic acid, Example 40(a), (0.50 g, 2.0mmol) and 1,4-benzodioxan-6-amine (0.33 g, 2.2 mmol, Aldrich) provided,after purification by silica gel chromatography (chloroform), the titleproduct as a yellow solid. MP 163-164° C. MS (ESI, pos. ion) m/z: 386(M+1).

EXAMPLE 41

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-2-methylprop-2-enamide

(a) (2E)-3-[4-(tert-Butyl)phenyl]-2-methylprop-2-enoic acid. Analogousto the procedure described for the preparation of Example 40, step (a),triethyl 2-phosphonopropionate (2.4 g, 10 mmol, Aldrich) and4-tert-butylbenzaldehyde (1.6 g, 10 mmol, Aldrich) provided the titleproduct as a yellow solid. MS (ESI, pos. ion) m/z: 219 (M+1).

(b)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-2-methylprop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[4-(tert-butyl)phenyl]-2-methylprop-2-enoic acid, Example 41(a),(0.44 g, 2.0 mmol) and 1,4-benzodioxan-6-amine (0.33 g, 2.2 mmol,Aldrich) provided, after purification by silica gel chromatography(chloroform), the title product as an off-white solid. MP 157-158° C. MS(ESI, pos. ion) m/z: 352 (M+1).

EXAMPLE 42

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-2-ethylprop-2-enamide

(a) (2E)-3-[4-(tert-Butyl)phenyl]-2-ethylprop-2-enoic acid. Analogous tothe procedure described for the preparation of Example 40, step (a),triethyl 2-phosphonobutyrate (2.5 g, 10 mmol, Aldrich) and4-tert-butylbenzaldehyde (1.6 g, 10 mmol, Aldrich) provided the titleproduct as a white solid. MS (ESI, pos. ion) m/z: 233 (M+1).

(b)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-2-ethylprop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[4-(tert-butyl)phenyl]-2-ethylprop-2-enoic acid, Example 42(a),(0.46 g, 2.0 mmol) and 1,4-benzodioxan-6-amine (0.33 g, 2.2 mmol,Aldrich) provided, after purification by silica gel chromatography(chloroform), the title product as a white solid. MP 133-134° C. MS(ESI, pos. ion) m/z: 366 (M+1).

EXAMPLE 43

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-(4-cyclopropylphenyl)prop-2-enamide

(a) Ethyl 4-cyclopropylbenzoate. To a round-bottomed flask under N₂ wasadded zinc dust (0.80 g, 12.5 mmol, Aldrich), cuprous chloride (1.23 g,12.5 mmol, Aldrich) and Et₂O (2 mL). The mixture was magneticallystirred and heated at reflux for 30 min. The suspension was treated withethyl 4-vinylbenzoate (0.85 g, 4.82 mmol, Apin) followed by methylenediiodide (1.68 g, 6.27 mmol, Aldrich) and reflux was continued for 24 h.The reaction mixture was allowed to cool to 25° C., filtered,concentrated in vacuo and purified by silica gel chromatography (9:1hexane:EtOAc) to provide the title product. MS (ESI, pos. ion) m/z: 191(M+1).

(b) 4-Cyclopropylbenzaldehyde. Ethyl 4-cyclopropylbenzoate, Example43(a), (316 mg, 1.66 mmol) was transferred to a round-bottomed flask andtreated with lithium aluminum hydride (0.30 mL, 3.0 mmol, 1.0 M in THF,Aldrich) under N₂. The reaction mixture was magnetically stirred at 25°C. for 1 h, then quenched by the dropwise addition of H₂O (0.5 mL)followed by 20% aq. KOH (3 mL). The suspension was filtered and theaqueous phase extracted with EtOAc. The organic extract was concentratedin vacuo and the crude alcohol was redissolved in anhydrous CH₂Cl₂ (2mL). In a separate round-bottomed flask, a solution of oxalyl chloride(2.0 mL, 4.0 mmol, 2.0 M in CH₂Cl₂, Aldrich) was magnetically stirredunder N₂ at −78° C. and treated dropwise with a solution of anhydrousdimethyl sulfoxide (4.0 mL, 56 mmol, Aldrich) in anhydrous CH₂Cl₂ (2mL). The reaction mixture was stirred at −78° C. for 5 min then treateddropwise with the solution of crude alcohol in CH₂Cl₂. The reactionmixture was stirred an additional 5 min at −78° C., treated withtriethylamine (2.0 mL, 14 mmol), allowed to warm to 25° C. and stirredat that temperature for 1 h. The reaction was quenched by the additionof H₂O and the mixture was extracted with Et₂O. The organic extract wasconcentrated in vacuo to provide 230 mg (95% over two steps) of thetitle product.

(c) (2E)-3-(4-Cyclopropylphenyl)prop-2-enoic acid. Analogous to theprocedure described for Example 40, step (a), 4-cyclopropylbenzaldehyde,Example 43(b), (0.23 g, 1.6 mmol) and triethyl phosphonoacetate (0.35 g,1.6 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z:189 (M+1).

(d)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-(4-cyclopropylphenyl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-(4-cyclopropylphenyl)prop-2-enoic acid, Example 43(c), (130 mg,0.69 mmol) and 1,4-benzodioxan-6-amine (104 mg, 0.69 mmol, Aldrich)provided, after purification by silica gel chromatography (65:35hexane:EtOAc), the title product as a clear glass. MS (ESI, pos. ion)m/z: 322 (M+1).

EXAMPLE 44

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[6-(tert-butyl)(3-pyridyl)]-prop-2-enamide

(a) 6-(tert-Butyl)pyridine-3-carbaldehyde. Analogous to the procedure ofRybakova, et al. Zh. Org. Khim. 1995, 31(5), 670-673,pyridine-3-methanol (2.18 g, 20.0 mmol, Aldrich), trimethylacetic acid(10.2 g, 100 mmol, Aldrich), silver nitrate (0.68 gm 4.0 mmol, Aldrich),and 10% aq. sulfuric acid (20 mL) were combined in a round-bottomedflask. The reaction mixture was magnetically stirred and treated with asolution of ammonium persulfate (9.1 g, 40 mmol, Aldrich) in H₂O (40mL). Evolution of gas was observed and the reaction mixture was stirredat 25° C. for 2 h. The reaction mixture was basified to pH 9 by theaddition of aq. ammonium hydroxide then extracted with EtOAc. Theorganic extract was washed with H₂O, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification of the crude product by silica gelchromatography (70:30 hexane:EtOAc) provided the title product. MS (ESI,pos. ion) m/z: 164 (M+1).

(b) (2E)-3-[6-(tert-Butyl)(3-pyridyl)]prop-2-enoic acid. Analogous tothe procedure described for Example 40, step (a),6-(tert-butyl)pyridine-3-carbaldehyde, Example 44(a), (0.55 g, 3.4 mmol)and triethyl phosphonoacetate (0.76 g, 3.4 mmol, Aldrich) provided thetitle product. MS (ESI, pos. ion) m/z: 206 (M+1).

(c)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (200mg, 1.0 mmol) and 1,4-benzodioxan-6-amine (150 mg, 1.0 mmol, Aldrich)provided, after purification by silica gel chromatography (60:40hexane:EtOAc), the title product as a clear glass. MS (ESI, pos. ion)m/z: 339 (M+1).

EXAMPLE 45

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[3-(tert-butyl)phenyl]prop-2-enamide

(a) 3-(tert-Butyl)benzaldehyde. To a round-bottomed flask equipped withmagnetic stirring was added 1-tert-butyl-3-methylbenzene (1 g, 6.8 mmol,Wiley), ammonium cerium (IV) nitrate (17.5 g, 29.7 mmol, Aldrich) and50% aq. acetic acid (150 mL). The reaction mixture was stirred andheated at 90° C. for 1.5 h. The reaction mixture was allowed to cool to25° C. and extracted with 10% EtOAc in hexane. The organic extract wasconcentrated in vacuo to provide the crude aldehyde.

(b) (2E)-3-[3-(tert-Butyl)phenyl]prop-2-enoic acid. Analogous to theprocedure described for Example 40, step (a),3-(tert-butyl)benzaldehyde, Example 45(a), (320 mg, 2.0 mmol) andtriethyl phosphonoacetate (250 mg, 2.0 mmol, Aldrich) provided the titleproduct. MS (ESI, pos. ion) m/z: 205 (M+1).

(c)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[3-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[3-(tert-butyl)phenyl]prop-2-enoic acid, Example 45(b), (200 mg,1.0 mmol) and 1,4-benzodioxan-6-amine (150 mg, 1.0 mmol, Aldrich)provided, after purification by silica gel chromatography (60:40hexane:EtOAc), the title product. MP 168° C. MS (ESI, pos. ion) m/z: 338(M+1).

EXAMPLE 46

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[2-fluoro-4-(trifluoromethyl)-phenyl]prop-2-enamide

(a) [2-Fluoro-4-(trifluoromethyl)phenyl]methan-1-ol. To a round-bottomedflask, equipped with magnetic stirring and a reflux condenser, was added2-fluoro-4-(trifluoromethyl)benzoic acid (5.0 g, 24 mmol, ABCR) andborane-THF complex (72 mL, 72 mmol, 1.0 M in THF, Aldrich) at 0° C.under N₂. The reaction mixture was warmed to 65° C. and stirred at thattemperature for 2 h. The reaction mixture was allowed to cool to 25° C.and the solvent was removed in vacuo. The resulting residue wasdissolved in CH₂Cl₂ (100 mL) and washed with satd Na₂CO₃ (100 mL). Theaqueous phase was back-extracted with CH₂Cl₂ (4×80 mL). The combinedorganic extract was washed with satd NaCl (200 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (gradient: 0-10% EtOAc in hexane) provided the titleproduct as a colorless oil.

(b) 2-Fluoro-4-(trifluoromethyl)benzaldehyde. To a solution of[2-fluoro-4-(trifluoromethyl)phenyl]methan-1-ol, Example 46(a), (4.4 g,23 mmol) in CH₂Cl₂ (100 mL) was added ground pyridinium dichromate (38.4g, 102 mmol, Fluka). The reaction mixture was stirred at 25° C.overnight, then filtered through Celite. The Celite pad was washed withCH₂Cl₂ (2×50 mL) and the combined filtrate was concentrated in vacuo.Purification by silica gel chromatography (gradient: 0-5% EtOAc inhexane) provided the title product as a white slurry.

(c) Methyl (2E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoate.2-Fluoro-4-(trifluoromethyl)benzaldehyde, Example 46(b), (900 mg, 4.7mmol) in CH₂Cl₂ (5 mL) was added via cannula to a solution ofcarbomethoxymethylene triphenylphosphorane (2.0 g, 6.1 mmol, Aldrich) inCH₂Cl₂ (15 mL), magnetically stirred in a round-bottomed flask at 0° C.The reaction mixture was allowed to warm to 25° C. and stirred at thistemperature under N₂ overnight. The solvent was removed in vacuo and thecrude material purified by silica gel chromatography (gradient: 0-5%EtOAc in hexane) to provide the title product as a white solid.

(d) (2E)-3-[2-Fluoro-4-(trifluoromethyl)phenyl]prop-2-enoic acid. Methyl(2E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoate, Example 46(c),(1.6 g, 6.3 mmol) was treated with lithium hydroxide monohydrate (530mg, 12.6 mmol, Aldrich) in wet EtOH (15 mL) and magnetically stirred ina round-bottomed flask at 25° C. overnight. The reaction mixture wasacidified to pH <2 with 10% aq. HCl and extracted with EtOAc (3×50 mL).The combined extracts were washed with satd NaCl (100 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to provide the acid as awhite solid.

(e)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example46(d), (200 mg, 0.85 mmol) and 1,4-benzodioxan-6-amine (193 mg, 1.28mmol, Aldrich) provided, after purification by silica gel chromatography(gradient: 0-20% EtOAc in hexane) and recrystallization from EtOAc andhexane, the title product as a yellow crystalline solid. MP 174-175° C.MS (ESI, pos. ion) m/z: 368 (M+1).

EXAMPLE 47

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[2,3-difluoro-4-(trifluoro-methyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 46, steps (b)-(e),the title product was obtained from2,3-difluoro-4-(trifluoromethyl)benzyl alcohol (ABCR) and1,4-benzodioxan-6-amine (Aldrich) as a crystalline yellow solid. MP169-170° C. MS (ESI, pos. ion) m/z: 386 (M+1).

EXAMPLE 48

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[2,4-bis(trifluoromethyl)-phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 46, steps (b)-(e),the title product was obtained from 2,4-bis(trifluoromethyl)benzylalcohol (Avocado) and 1,4-benzodioxan-6-amine (Aldrich) as a crystallineyellow solid. MP 204-205° C. MS (ESI, pos. ion) m/z: 418 (M+1).

EXAMPLE 49

(2E)-3-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide

Analogous to the procedure used to prepare Example 46, steps (a)-(e),the title product was obtained from 2-fluoro-4-(trifluoromethyl)benzoicacid (ABCR) and 5-aminoindole (Aldrich) as a crystalline yellow solid.MP 203-205° C. MS (ESI, pos. ion) m/z: 349 (M+1).

EXAMPLE 50

(2E)-3-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide

Analogous to the procedure used to prepare Example 46, steps (b)-(e),the title product was obtained from2,3-difluoro-4-(trifluoromethyl)benzyl alcohol (ABCR) and 5-aminoindole(Aldrich) as a crystalline yellow solid. NM 220-222° C. MS (ESI, pos.ion) m/z: 367 (M+1).

EXAMPLE 51

(2E)-3-[2,4-Bis(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide

Analogous to the procedure used to prepare Example 46, steps (b)-(e),the title product was obtained from 2,4-bis(trifluoromethyl)benzylalcohol (Avocado) and 5-aminoindole (Aldrich) as a crystalline yellowsolid. MP 207-209° C. MS (ESI, pos. ion) m/z: 399 (M+1).

EXAMPLE 52

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide

(a). Ethyl 3-[4-(tert-butyl)phenyl]prop-2-ynoate. To a 1 Lround-bottomed flask was added (4-tert-butyl)phenylacetylene (33.8 g,214 mmol, GFS Chemicals) and anhydrous THF (220 mL). The solution wasmagnetically stirred, purged with N₂ and cooled to −78° C., thenn-butyllithium (136 mL, 2.5 M in hexanes, Aldrich) was added slowly.After the addition was complete, the mixture was gradually warmed to 0°C. and stirred magnetically for 30 min. The reaction mixture was cooledto −78° C. again and ethyl chloroformate (28.6 mL, 299.2 mmol, Aldrich)was added. After allowing to warm to 25° C. and stirring overnight, thereaction was quenched with 1:1 satd NaHCO₃:satd NH₄Cl (200 mL) andextracted with Et₂O (1000 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to afford a yellow oil. Purificationby silica gel chromatography (gradient: 0.5%-3% EtOAc/hexane) providedethyl 3-[4-(tert-butyl)phenyl]prop-2-ynoate as a pale yellow oil. MS(ESI, pos. ion) m/z: 231 (M+1).

(b). Ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate. Accordingto the procedure of E. Piers et al., Can. J. Chem. 1994, 72, 1816, to a150 mL round-bottomed flask equipped with a reflux condenser andmagnetic stirring was added ethyl 3-[4-(tert-butyl)phenyl]prop-2-ynoate,Example 52(a), (15 g, 65 mmol), sodium iodide (31 g, 209 mmol, Aldrich)and glacial acetic acid (48 mL, 830 mmol). The reaction mixture waspurged with N₂ and the flask immersed in a pre-heated 115° C. oil bath.The reaction mixture was magnetically stirred at 115° C. for 4 h, thenallowed to cool to 25° C. and treated with H₂O (200 mL). The aqueousphase was extracted with Et₂O (500 mL). The organic layer was washedwith satd Na₂CO₃ until the evolution of CO₂ ceased, then washed with 1 MNa₂S₂O₃ (100 mL), satd NaCl, dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide ethyl(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate as a yellow oil. MS(ESI, pos. ion) m/z: 359 (M+1).

(c) Ethyl(2Z)-3-[4-(tert-butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enoate.To a 100 mL round-bottomed flask equipped with a reflux condenser andmagnetic stirring was added ethyl(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate, Example 52(b), (0.75g, 2.1 mmol), 4-trifluoromethylphenylboronic acid (0.60 g, 3.1 mmol,Aldrich), tetrakis(triphenylphosphine)palladium (0) (0.24 g, 0.21 mmol,Aldrich), toluene (10 mL), EtOH (2 mL), and 2 M aq. Na₂CO₃ (2 mL). Thereaction mixture was magnetically stirred at 80° C. under N₂ overnight,allowed to cool to 25° C. and diluted with EtOAc (50 mL). The organiclayer was separated, washed with H₂O, satd NaCl (50 mL), dried overNa₂SO₄, filtered and concentrated to afford a brown oil. Purification bysilica gel chromatography (gradient: 1.5%-2% EtOAc/hexane) provided thetitle product as a white solid. MS (ESI, pos. ion) m/z: 377 (M+1).

(d)(2Z)-3-[4-(tert-Butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enoicacid. To a 50 mL round-bottomed flask equipped with a reflux condenserwas added ethyl(2Z)-3-[4-(tert-butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enoate,Example 52(c), (0.74 g, 2.0 mmol), 1,4-dioxane (3 mL), KOH (0.66 g, 12mmol) and H₂O (1.5 mL). The reaction mixture was heated and magneticallystirred under reflux overnight then diluted with H₂O (20 mL) andacidified with 1 N HCl. The aqueous mixture was extracted with CH₂Cl₂(3×100 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo to provide the title product as a white solid. MS(ESI, pos. ion) m/z: 349 (M+1).

(e)N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2Z)-3-[4-(tert-butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enoicacid, Example 52(d), (0.15 g, 0.43 mmol) and 1,4-benzodioxan-6-amine(0.07 g, 0.43 mmol, Aldrich) provided, after purification by silica gelchromatography (gradient: 10%-18% EtOAc/hexane), the title product as apale yellow solid. MP 150-151° C. MS (ESI, pos. ion) m/z: 482 (M+1).

EXAMPLE 53

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enamide

(a) Ethyl (2E)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enoate. A solutionof ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate, Example52(b), (710 mg, 2.0 mmol) in anhydrous DMF (4 mL) was added dropwise tobenzylzinc bromide (12 mL, 6.0 mmol, 0.5 M solution in TBF, Aldrich)magnetically stirred under Ar at 0° C. in a round-bottomed flask. Themixture was treated with bis(acetonitrile)dichloropalladium (II) (78 mg,0.30 mmol, Aldrich) in one portion. The reaction mixture was thenmagnetically stirred for 16 h at 25° C., diluted with Et₂O (100 mL) andwashed with 1N HCl (25 mL) and satd NaCl (25 mL). The organic phase wasdried over MgSO₄, filtered and concentrated in vacuo and the residuepurified by silica gel chromatography (49:1 hexane:EtOAc) to provide thetitle product as a colorless oil. MS (ESI, pos. ion) m/z: 323 (M+1).

(b) (2E)-3-[4-(tert-Butyl)phenyl]-4-phenylbut-2-enoic acid. Ethyl(2E)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enoate, Example 53(a), (530mg, 1.8 mmol) was treated with KOH (0.22 g, 4.0 mmol), H₂O (4 mL) and1,4-dioxane (2 mL), then magnetically stirred under reflux for 16 h. Thereaction mixture was diluted with H₂O (50 mL), acidified with 1 N HCland extracted with chloroform. The combined organic extract was washedwith satd NaCl, dried over MgSO₄, filtered and concentrated in vacuo.The resulting residue was crystallized from EtOAc and hexane to providethe title product as a white solid.

(c)(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enoic acid, Example 53(b),(250 mg, 0.85 mmol) and 1,4-benzodioxan-6-amine (140 mg, 0.93 mmol,Aldrich) provided, after purification by silica gel chromatography(chloroform), the title product as off-white needles. MP 97-99° C. MS(ESI, pos. ion) m/z: 428 (M+1).

EXAMPLE 54

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-5-methylhex-2-enamide

Analogous to the procedure used to prepare Example 53, starting from3-methylbutylzinc bromide (Aldrich), ethyl(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate, Example 52(b), and1,4-benzodioxan-6-amine (Aldrich), the title product was obtained as anoff-white solid. MP 123° C. MS (ESI, pos. ion) m/z: 394 (M+1).

EXAMPLE 55

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enamide

(a) 3-[4-(tert-Butyl)phenyl]prop-2-ynoic acid. To a round-bottomed flaskequipped with magnetic stirring and a reflux condenser was added asolution of ethyl 3-[4-(tert-butyl)phenyl]prop-2-ynoate, Example 52(a),(4.6 g, 20 mmol) in 1,4-dioxane (5 mL). The solution was treated withH₂O (15 mL) and KOH (2.2 g, 40 mmol) then stirred and heated at refluxunder Ar for 18 h. After allowing to cool to 25° C., the mixture wasdiluted with H₂O (200 mL) and washed with Et₂O (50 mL). The aqueousphase was separated, acidified with 1 N HCl and extracted withchloroform. The chloroform extract was washed with satd NaCl, dried overMgSO₄, filtered and concentrated in vacuo. Crystallization from EtOAcand hexane provided the title product as white needles. MS (ESI, pos.ion) m/z: 203 (M+1).

(b)N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-ynamide.Analogous to the procedure used to prepare Example 1,3-[4-(tert-butyl)phenyl]prop-2-ynoic acid, Example 55(a), (404 mg, 2.0mmol) and 1,4-benzodioxan-6-amine (330 mg, 2.2 mmol, Aldrich) providedthe title product as a white solid. MP 199° C. MS (ESI, pos. ion) m/z:336 (M+1).

(c)N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enamide.Analogous to the procedure described for the preparation of Example52(b),N-(2H,3H-benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-ynamide,Example 55(b), (0.335 g, 1.0 mmol), sodium iodide (0.48 g, 3.2 mmol,Aldrich) and glacial acetic acid (0.73 mL) provided, after purificationby silica gel chromatography (chloroform), the title product as yellowcrystals. MP 164° C. MS (ESI, pos. ion) m/z: 464 (M+1).

EXAMPLE 56

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-(3-aminophenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 52, step (c),3-aminophenylboronic acid (0.23 g, 1.5 mmol, Avocado) andN-(2H,3H-benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enamide,Example 55, (0.46 g, 1.0 mmol) provided the title product as off-whitecrystals. MP 140° C. MS (ESI, pos. ion) m/z: 429 (M+1).

EXAMPLE 57

Ethyl(4E)-5-(N-(2H,3H-benzo[e]1,4-dioxan-6-yl)carbamoyl)-4-[4-(tert-butyl)phenyl]pent-4-enoate

Analogously to the procedure used to prepare Example 53, step (a),3-ethoxy-3-oxopropylzinc bromide (6.0 mL, 3.0 mmol, 0.5 M in THF,Aldrich) andN-(2H,3H-benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enamide,Example 55, (0.46 g, 1.0 mmol) provided the title product as a paleyellow solid. MP 104-105° C. MS (ESI, pos. ion) m/z: 438 (M+1).

EXAMPLE 58

3-Methoxyphenyl (2E)-3-[4-(tert-butyl)phenyl]prop-2-enoate. To a 100 mLround-bottomed flask equipped with magnetic stirring was added4-tert-butyl-trans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie),CH₂Cl₂ (10 mL), and DMF (10 uL) under N₂. The solution was treateddropwise with oxalyl chloride (4.0 mL, 8.0 mmol, 2.0 M in CH₂Cl₂,Aldrich) then stirred at 25° C. for 1 h. The reaction mixture wasconcentrated in vacuo and the residue treated with 3-methoxyphenol (269uL, 2.45 mmol, Aldrich), THF (20 mL) and satd K₂CO₃ (15 mL). Thereaction mixture was stirred at 25° C. overnight, then acidified to pH4.5 with 1 N HCl. The mixture was extracted with EtOAc (2×30 mL), thecombined organic extract was dried and concentrated in vacuo.Purification by silica gel chromatography (5:1 hexane:EtOAc) providedthe title product as a white solid. MP 83° C. MS (ESI, pos. ion) m/z:311 (M+1).

EXAMPLE 60

N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-hydroxyprop-2-enamide

(a) tert-Butyl3-[4-(tert-butyl)phenyl]-3-hydroxypropanoate. To around-bottomed flask equipped with magnetic stirring was addedN,N-diisopropylamine (10.4 mL, 74.0 mmol, Aldrich) and anhydrous THF (20mL). The solution was stirred at −78° C. under N₂ and treated dropwisewith n-butyllithium (30.0 mL, 75.0 mmol, 2.5 M in hexane, Aldrich).After stirring for 10 min at −78° C., the reaction mixture was treatedwith t-butyl acetate (10.8 mL, 80.1 mmol, Aldrich). After stirring 30min at −78° C., the enolate was added via cannula to a solution of4-t-butylbenzaldehyde (10.0 g, 61.6 mmol, Fluka) in anhydrous THF (100mL), stirred under N₂ at −78° C. The reaction mixture was allowed towarm to 0° C. with stirring over 3 h, then quenched with satd NHFCl andconcentrated in vacuo to remove the THF. The resulting mixture wasdiluted with satd NH₄Cl (100 mL) and extracted with Et₂O (200 mL). Theorganic extract was washed with H₂O (100 mL), satd NaCl (50 mL), driedover MgSO₄, filtered and concentrated in vacuo to provide the titleproduct as a white solid. MS (ESI, pos. ion) m/z: 261 (M+1-H₂O).

(b) tert-butyl 3-[4-(tert-butyl)phenyl]-3-oxopropanoate. tert-Butyl3-[4-(tert-butyl)phenyl]-3-hydroxypropanoate, Example 60(a), (5.0 g, 18mmol) was dissolved in CH₂Cl₂ (100 mL), magnetically stirred in around-bottomed flask at 0° C., and treated with pyridiniumchlorochromate (5.8 g, 27 mmol, Aldrich) in portions. The reactionmixture was allowed to warm to 25° C. and stirred at that temperaturefor 5 h. The mixture was filtered through a pad of Celite, thefiltercake washed with CH₂Cl₂ (3×100 mL) and the combined filtrate wasconcentrated in vacuo. Purification by silica gel chromatography (1:1hexane:EtOAc) provided the title product as a dark oil. MS (ESI, pos.ion) m/z: 277 (M+1).

(c)N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-hydroxyprop-2-enamide.According to the procedure of Wiseman et al., J. Org. Chem. 1991, 56,1713-1718, to a round-bottomed flask equipped with magnetic stirring anda reflux condenser was added tert-butyl3-[4-(tert-butyl)phenyl]-3-oxopropanoate, Example 60(b), (640 mg, 2.3mmol), 1,4-benzodioxan-6-amine (350 mg, 2.3 mmol, Aldrich) and anhydroustoluene (20 mL). The mixture was stirred and heated at 130° C. for 2 h.Upon allowing to cool to 25° C., a precipitate was observed. Hexane (20mL) was added to the suspension and the precipitate collected byfiltration, washed with hexane (20 mL) and dried in vacuo at 60° C. toprovide the title product as a pale grey solid. MP 161° C. MS (ESI, pos.ion) m/z: 354 (M+1).

EXAMPLE 61

N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)[7-(tert-butyl)(3-isoquinolyl)]-carboxamide

(a)2-[(tert-Butyl)oxycarbonyl]-7-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid. According to the procedure of D. Ma, et al., Bioorg. Med. Chem.Lett. 1998, 8(18), 2447-2450, to a 250 mL round-bottomed flask, equippedwith magnetic stirring and reflux condenser, was addedN-Boc-(p-tert-butyl)-S-phenylalanine (5.0 g, 15.6 mmol, Bachem),formaldehyde (50 mL, 37 wt. % in H₂O, Aldrich) and cond HCl (30 mL). Thereaction mixture was stir-red and heated at 90° C. for 4 h. The solventswere removed in vacuo to provide 3.6 g of a residue [MS (ESI, pos. ion)m/z: 234 (M+1)] which was dissolved in THF (140 mL) and treated with 5%aq. K₂CO₃ (140 mL) and di-t-butyl dicarbonate (4.8 g, 22 mmol, Aldrich).The reaction mixture was stirred at 25° C. overnight, then acidified topH 5 with 1 N HCl. The mixture was extracted with EtOAc (300 mL), theorganic phase washed with satd NaCl (100 mL) and H₂O (120 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by silicagel chromatography (2:1 hexane:EtOAc) provided the title product. MS(ESI, pos. ion) m/z: 334 (M+1).

(b)N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)[7-(tert-butyl)(3-1,2,3,4-tetrahydroisoquinolyl)]carboxamidehydrochloride. To a 250 mL round-bottomed flask equipped with magneticstirring was added2-[(tert-butyl)oxycarbonyl]-7-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid, Example 61(a), (1.5 g, 4.65 mmol), DMF (15 mL),1,4-benzodioxan-6-amine (700 mg, 4.65 mmol, Aldrich),dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (1.25 g, 6.5 mmol,Aldrich) and N,N-diisopropylethylamine (2.5 mL, 13.95 mmol, Aldrich).The reaction mixture was stirred at 25° C. overnight then concentratedin vacuo. The residue was dissolved in EtOAc (35 mL), washed with H₂O(2×15 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (3:1 hexane:EtOAc) provided aproduct [MS (ESI, pos. ion) m/z: 467 (M+1)] which was treated with 4.0 NHCl in 1,4 dioxane (10 mL, Aldrich) and stirred at 25° C. for 1 h. Thesolvent was removed in vacuo to provide the title product as thehydrochloride salt. MP 134° C. MS (ESI, pos. ion) m/z: 367 (M+1).

(c)N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)[7-(tert-butyl)(3-isoquinolyl)]-carboxamide.Analogous to the procedure of E. D. Cox; T. J. Hagen; R. M. McKernan; J.M. Cook, Med. Chem. Rest. 1995, 5(9), 710-718,N-(2H,3H-benzo[3,4-e]1,4-dioxan-6-yl)[7-(tert-butyl)(3-1,2,3,4-tetrahydroisoquinolyl)]carboxamidehydrochloride, Example 61(b), was suspended in EtOAc (55 mL), washedwith 10% NaHCO₃ (20 mL) and H₂O (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue (80 mg, 0.22 mmol) wasdissolved in toluene (10 mL) and treated with manganese dioxide (110 mg,1.1 mmol). The reaction mixture was magnetically stirred at 70° C. underN₂ for 1.5 h, filtered through Celite and concentrated in vacuo.Purification by silica gel chromatography (8:1 hexane:EtOAc) providedthe title product as a yellow solid. MP 154-157° C. MS (ESI, pos. ion)m/z: 363 (M+1).

EXAMPLE 63

N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) (2Z)-3-[4-(tert-Butyl)phenyl]prop-2-enoic acid. Potassiumbis(trimethylsilyl)amide (6.1 mL, 3.05 mmol, 0.5 M in toluene, Aldrich)was added dropwise with stirring to a mixture of diphenylphosphonoaceticacid ethyl ester (0.98 g, 3.05 mmol, TCI-US) and 18-crown-6 (3.35 g,12.7 mmol, Aldrich) in anhydrous THF (20 mL), magnetically stirred at−78° C. under Ar. The reaction mixture was stirred at −78° C. for 0.5 hthen treated dropwise with a solution of 4-tert-butylbenzaldehyde (0.42mL, 2.54 mmol, Aldrich) in anhydrous THF (5 mL). The mixture was stirredat −78° C. for 1 h, quenched with satd NH₄Cl (5 mL), warmed to 25° C.,diluted with H₂O (50 mL) and extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with satd NaCl, dried over MgSO₄,filtered and concentrated in vacuo to provide a brown viscous oil. [MS(ESI, pos. ion) m/z: 233 (M+1)] The oil (0.83 g) was dissolved in THF (5mL) and MeOH (5 mL), magnetically stirred in a round-bottomed flask at25° C., and treated with 1 N LiOH (10 mL). The reaction mixture wasstirred at 25° C. for 18 h, the organic solvents removed in vacuo, andthe aqueous phase was washed with Et₂O, acidified with 10% citric acidand extracted with EtOAc (3×10 mL). The combined organic extracts weredried over MgSO₄, filtered and concentrated in vacuo to provide thetitle product as a white solid. MS (ESI, pos. ion) m/z: 205 (M+1).

(b)N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2Z)-3-[4-(tert-butyl)phenyl]prop-2-enoic acid, Example 63(a), (0.46 g,2.3 mmol) and 1,4-benzodioxan-6-amine (0.38 g, 2.58 mmol, Aldrich)provided the title product as a white solid. MP 114-116° C. MS (ESI,pos. ion) m/z: 338 (M+1).

EXAMPLE 64

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-phenylprop-2-enamide

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-ynamide,Example 55(b), (0.34 g, 1.0 mmol) was dissolved in anhydrous EtOAc (50mL) in a 100 mL round-bottomed flask equipped with reflux condenser andmagnetic stirring under dry nitrogen atmosphere. To this solution wasadded iodobenzene (0.20 g, 1.0 mmol, Aldrich) andbis(dibenzylideneacetone)palladium (0.080 g, 0.14 mmol, Acros), followedby diethylamine (0.34 mL, 3.3 mmol, Aldrich) and formic acid (0.098 mL,2.6 mmol, Aldrich). The reaction mixture was heated under reflux for 20h, cooled to room temperature, washed with 1 N HCl (2×5 mL), 1 N NaOH(2×5 mL), satd NaCl (5 mL) and dried over Na₂SO₄. The organic solutionwas filtered and concentrated to afford a brown oil which was purifiedby silica gel chromatography (20 % EtOAc/hexane) to give the titlecompound as a pale yellow solid. MP 80-82° C. MS (ESI, pos. ion) m/z:414 (M+1).

EXAMPLE 65

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-3-phenylprop-2-enamide

(a). N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-phenylprop-2-ynamide. Analogousto the procedure used to prepare Example 1, phenylpropiolic acid (5.8 g,140 mmol, Aldrich) and 1,4-benzodioxan-6-amine (6.65 g, 44 mmol,Aldrich) provided, after recrystallization from EtOAc and hexane, thetitle compound as a white solid. MP 132° C. MS (ESI, pos. ion) m/z: 280(M+1).

(b).(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-3-phenylprop-2-enamide.Analogous to the procedure used to prepare Example 64,1-tert-butyl-4-iodobenzene (0.26 g, 1.0 mmol, Aldrich) andN-(2H,3H-benzo[e]1,4-dioxan-6-yl)-3-phenylprop-2-ynamide, Example 65(a),(0.28 g, 1.0 mmol) provided, after recrystallization from EtOAc andhexane, the title compound as an off-white solid. MP 139° C. MS (ESI,pos. ion) m/z: 414 (M+1).

EXAMPLE 66

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(N-methylcarbamoyl)(1H-indazol-6-yl)]prop-2-enamide

To a round-bottomed flask, equipped with a magnetic stir bar, was added(2E)-N-(1H-indazol-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide, Example155, (61 mg, 0.19 mmol), THF (8 mL) and isocyanatomethane (54 mg, 0.96mmol, Carbolabs). The reaction mixture was stirred at room temperaturefor 8 h. The reaction mixture was diluted with EtOAc (10 mL), washedwith water (8 mL), dried over Na₂SO₄, filtered and concentrated invacuo. Purification by silica gel chromatography (40:20:1hexane:EtOAc:MeOH) provided the title product as an off-white solid. MN208-209° C. MS (ESI, pos. ion) m/z: 377 (M+1).

EXAMPLE 67

(2E)-3-[4-(tert-Butyl)phenyl]-N-{4-chloro-3-[(methylamino)carbonylamino]-phenyl}prop-2-enamide

(a)(2E)-N-(3-Amino-4-chlorophenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide.To a round-bottomed flask equipped with a magnetic stir bar, was added(2E)-3-[4-(tert-butyl)phenyl]-N-(4-chloro-3-nitrophenyl)prop-2-enamide,Example 156, (250 mg, 0.69 mmol), EtOH (8 mL), indium (800 mg, 6.9 mmol,Aldrich) and satd NH₄Cl (10 mL). The reaction mixture was stirred atreflux for 5 h. The solvents were removed in vacuo, the residue wasdissolved in EtOAc (20 mL), washed with water (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to yield the title product.MS (ESI, pos. ion) m/z: 329 (M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-{4-chloro-3-[(methylamnino)-carbonylamino]phenyl}prop-2-enamide.According to the procedure used to prepare Example 66,(2E)-N-(3-amino-4-chlorophenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide,Example 67(a), (90 mg, 0.27 mmol) and isocyanatomethane (156 mg, 2.7mmol, Carbolabs) provided, after purification by silica gelchromatography (2:1 hexane:EtOAc), the title product as an off-whitesolid. MP 120-122° C. MS (ESI, pos. ion) m/z: 386 (M+1).

EXAMPLE 68

(2E)-3-[4-(tert-Butyl)phenyl]-N-quinoxalin-6-ylprop-2-enamide

(a) Quinoxaline-6-ylamine. To a round-bottomed flask equipped withmagnetic stirring was added 4-nitro-1,2-phenylenediamine (1.0 g, 6.5mmol, Aldrich), acetonitrile (10 mL) and glyoxal (2.2 mL, 19 mmol, 40wt. % in water, Aldrich). The reaction mixture was allowed to stir at50° C. for 12 h, then concentrated in vacuo to yield 1.1 g crude6-nitro-quinoxaline. The crude product was dissolved in methanol,treated with 10% Pd/C (10 mg, Aldrich) and stirred under H₂ (1 atm) at25° C. overnight. The reaction mixture was filtered through Celite andthe filtrate was concentrated in vacuo to provide the title product. MS(ESI, pos. ion) m/z: 146 (M+1).

(b) (2E)-3-[4-(tert-Butyl)phenyl]-N-quinoxalin-6-ylprop-2-enamide.Analogous to the procedure used to prepare Example 2,4-tert-butyl-trans-cinnamic acid (100 mg, 0.40 mmol, EMKA-Chemie) andquinoxaline-6-ylamine, Example 68(a), (71 mg, 0.40 mmol) provided, afterpurification by silica gel chromatography (1:2 hexane:EtOAc), the titleproduct as a yellow solid. MP 229-230° C. MS (ESI, pos. ion) m/z: 332(M+1).

EXAMPLE 69

(2E)-N-(1-acetyl(7-1,2,3,4-tetrahydroquinolyl))-3-[4-(tert-butyl)phenyl]prop-2-enamide

(a) 1-Acetyl-7-nitro-1,2,3,4-tetrahydroquinoline. A mixture of7-nitro-1,2,3,4-tetrahydroquinoline, Example 19(a), (0.36 g, 2.0 mmol)and acetic anhydride (3.5 mL, 37 mmol, Aldrich) in a 15 mLround-bottomed flask, was heated at reflux for 1.5 h. The reactionmixture was concentrated in vacuo and the residue was partitionedbetween EtOAc and 30% ammonium hydroxide. The aqueous layer wasextracted with EtOAc (10 mL) and the combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound as a yellow solid. MS (ESI, pos. ion) m/z: 221 (M+1).

(b) 1-Acetyl-7-amino-1,2,3,4-tetrahydroquinoline. Analogous to theprocedure used to prepare Example 3, step (a),1-acetyl-7-nitro-1,2,3,4-tetrahydroquinoline, Example 69(a), (0.44 g,2.0 mmol) was converted to the title product. MS (ESI, pos. ion) m/z:191 (M+1).

(c)(2E)-N-(1-acetyl(7-1,2,3,4-tetrahydroquinolyl))-3-[4-(tert-butyl)phenyl]prop-2-enamide.According to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (0.41 g, 2.0 mmol, EMKA Chemie) and1-acetyl-7-amino-1,2,3,4-tetrahydroquinoline, Example 69(b), (370 mg,2.0 mmol) provided, after purification by silica gel chromatography (1:1hexane:EtOAc), the title compound as an amorphous white solid. MS (ESI,pos. ion) m/z: 377 (M+1).

EXAMPLE 70

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-methoxyethyl)indol-6-yl]prop-2-enamide

To a round-bottomed flask was added,(2E)-3-[4-(tert-butyl)phenyl]-N-indol-6-ylprop-2-enamide, Example 189,(320 mg, 1.0 mmol) and anhydrous DMF (20 mL). The solution was stirredmagnetically and treated with sodium hydride (0.10 g, 2.5 mmol, 60%dispersion in mineral oil, Aldrich) followed by 2-bromoethyl methylether (140 mg, 1.0 mmol, Aldrich). Stirring was continued at 25° C. for2 h, then the reaction mixture was quenched by the addition of water (50mL) and extracted with EtOAc. The organic extract was concentrated invacuo. Purification by silica gel chromatography (60:40 hexane:EtOAc)provided the title compound as a yellow solid. MP 133° C. MS (ESI, pos.ion) m/z: 377 (M+1).

EXAMPLE 71

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-methoxyethyl)indol-5-yl]prop-2-enamide

Analogous to the procedure used to prepare Example 70, 2-bromoethylmethyl ether (140 mg, 1.0 mmol, Aldrich) and(2E)-3-[4-(tert-butyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 161,(320 mg, 0.01 mmol) provided, after purification by silica gelchromatography (65:35 hexane:EtOAc), the title compound as a pale yellowsolid. MP 138° C. MS (ESI, pos. ion) m/z: 377 (M+1).

EXAMPLE 72

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-hydroxyethyl)indol-6-yl]prop-2-enamide

(a) 1-[2-(1,1,2,2-Tetramethyl-1-silapropoxy)ethyl]indole-6-ylamine.Analogous to the procedure used to prepare Example 33, step (a),6-nitroindole (0.49 g, 3.0 mmol, Aldrich) and(2-bromoethoxy)-tert-butyldimethylsilane (0.72 g, 3.0 mmol, Aldrich)provided the title product. MS (ESI, pos. ion) m/z: 291 (M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-6-yl}prop-2-enamide.Analogous to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indole-6-ylamine, Example72(a), (290 mg, 1.0 mmol) provided the title product. MS (ESI, pos. ion)m/z: 477 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-hydroxyethyl)indol-6-yl]prop-2-enamide.(2E)-3-[4-(tert-Butyl)phenyl]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-6-yl}prop-2-enamide,Example 72(b), (420 mg, 0.88 mmol) was transferred to a round-bottomedflask and treated with tetrabutylammonium fluoride (2.0 mL, 2.0 mmol,1.0 M in THF, Aldrich) under N₂. The reaction mixture was magneticallystirred at 25° C. for 2 h. The reaction mixture was diluted with water(25 mL) and extracted with EtOAc. The organic extract was concentratedin vacuo. Purification by silica gel chromatography (30:70 hexane:EtOAc)provided the title compound as a yellow solid. MP 178° C. MS (ESI, pos.ion) m/z: 363 (M+1).

EXAMPLE 73

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-hydroxyethyl)indol-5-yl]prop-2-enamide

(a) 1-[2-(1,1,2,2-Tetramethyl-1-silapropoxy)ethyl]indole-5-ylamine.According to the procedure used to prepare Example 33, step (a),5-nitroindole (0.49 g, 3.0 mmol, Aldrich) and(2-bromoethoxy)-tert-butyldimethylsilane (0.72 g, 3.0 mmol, Aldrich)provided the title product. MS (ESI, pos. ion) m/z: 291 (M+1).

(b)(2E)-3-[4-(tert-Butyl)phenyl]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-5-yl}prop-2-enamide.According to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (100 mg, 0.50 mmol, EMKA-Chemie) and1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indole-5-ylamine, Example73(a), (145 mg, 0.50 mmol) provided the title product. MS (ESI, pos.ion) m/z: 477 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-hydroxyethyl)indol-5-yl]prop-2-enamide.According to the procedure used to prepare Example 72, step (c),(2E)-3-[4-(tert-butyl)phenyl]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-5-yl}prop-2-enamide,Example 73(b), (130 mg, 0.27 mmol) and tetrabutylammonium fluoride(1.0mL, 1.0 mmol, 1.0 M in THF, Aldrich) provided, after purification bysilica gel chromatography (30:70 hexane:EtOAc), the title compound as apale yellow solid. MP 182° C. MS (ESI, pos. ion) m/z: 363 (M+1).

EXAMPLE 74

(2E)-3-[4-(tert-Butyl)phenyl]-N-[2-(hydroxymethyl)indol-5-yl]prop-2-enamide

(a) Ethyl 5-aminoindole-2-carboxylate. Analogous to the procedure usedto prepare Example 3, step (a), ethyl 5-nitroindole-2-carboxylate (2.3g, 9.9 mmol, Acros) provided the title product. MS (ESI, pos. ion) m/z:205 (M+1).

(b) (5-Aminoindol-2-yl)methan-1-ol. Ethyl 5-aminoindole-2-carboxylate,Example 74(a), (1.5 g, 7.3 mmol) was transferred to a round-bottomedflask and treated with lithium aluminum hydride (10 mL, 10 mmol, 1.0 Min THF, Aldrich) under N₂. The reaction mixture was magnetically stirredat 25° C. for 1 h, then quenched by the dropwise addition of H₂O (0.5mL) followed by 20% aq. KOH (30 mL). The suspension was filtered and theaqueous phase extracted with EtOAc. The organic extract was concentratedin vacuo. Purification of the crude product by silica gel chromatography(20:80 hexane:EtOAc) provided the title product. MS (ESI, pos. ion) m/z:163 (M+1).

(c)(2E)-3-[4-(tert-Butyl)phenyl]-N-[2-(hydroxymethyl)indol-5-yl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and(5-aminoindol-2-yl)methan-1-ol, Example 74(b), (160 mg, 1.0 mmol)provided, after purification by silica gel chromatography (40:60hexane:EtOAc), the title product as a pale tan amorphous solid. MS (ESI,pos. ion) m/z: 349 (M+1).

EXAMPLE 75

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enamide

(a) Ethyl 6-(tert-butyl)-2-methylpyridine-3-carboxylate. Analogous tothe procedure used to prepare Example 44, step (a), ethyl2-methylnicotinate (8.3 g, 50 mmol, Aldrich), trimethylacetic acid (26g, 250 mmol, Aldrich), silver nitrate (1.7 g, 10 mmol, Aldrich), 10% aq.sulfuric acid (50 mL) and ammonium persulfate (23 g, 100 mmol, Aldrich)provided, after purification by silica gel chromatography (80:20hexane:EtOAc), the title product. MS (ESI, pos. ion) m/z: 222 (M+1).

(b) 6-(tert-Butyl)-2-methylpyridine-3-carbaldehyde. Analogous to theprocedure used to prepare Example 43, step (b), ethyl6-(tert-butyl)-2-methylpyridine-3-carboxylate, Example 75(a), (5.2 g, 23mmol) provided the title product. MS (ESI, pos. ion) m/z: 178 (M+1).

(c) (2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid.Analogous to the procedure used to prepare Example 40, step (a),6-(tert-butyl)-2-methylpyridine-3-carbaldehyde, Example 75(b), (3.0 g,17 mmol) and triethyl phosphonoacetate (4.0 g, 18 mmol, Aldrich)provided the title product. MS (ESI, pos. ion) m/z: 220 (M+1).

(d)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example75(c), (110 mg, 0.50 mmol) and 1,4-benzodioxan-6-amine (76 mg, 0.50mmol, Aldrich) provided, after purification by silica gel chromatography(55:45 hexane:EtOAc), the title compound as a yellow amorphous solid. MS(ESI, pos. ion) m/z: 353 (M+1).

EXAMPLE 76

(2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)]-N-indol-6-ylprop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example75(c), (220 mg, 1.0 mmol) and 6-aminoindole (130 mg, 1.0 mmol,Lancaster) provided, after purification by silica gel chromatography(55:45 hexane:EtOAc), the title compound as a yellow solid. MP 182° C.MS (ESI, pos. ion) m/z: 334 (M+1).

EXAMPLE 77

(2E)-N-Benzothiazol-6-yl-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example75(c), (220 mg, 1.0 mmol) and 6-aminobenzothiazole (150 mg, 1.0 mmol,Lancaster) provided, after purification by silica gel chromatography(55:45 hexane:EtOAc), the title compound as a pale yellow amorphoussolid. MS (ESI, pos. ion) m/z: 352 (M+1).

EXAMPLE 78

(2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)]-N-indol-5-ylprop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example75(c), (0.88 g, 4.0 mmol) and 5-aminoindole (0.53 g, 4.0 mmol,Lancaster) provided, after purification by silica gel chromatography(55:45 hexane:EtOAc), the title compound as a yellow amorphous solid. MS(ESI, pos. ion) m/z: 334 (M+1).

EXAMPLE 79

(2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)]-N-[2-(hydroxymethyl)indol-5-yl]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example75(c), (110 mg, 0.50 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example74(b), (81, 0.50 mmol) provided, after purification by silica gelchromatography (25:75 hexane:EtOAc), the title compound as a pale yellowsolid. MP 213° C. MS (ESI, pos. ion) m/z: 364 (M+1).

EXAMPLE 80

(2E)-3-[6-(tert-Butyl)(3-pyridyl)]-N-[2-(hydroxymethyl)indol-5-yl]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (41mg, 0.20 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example 74(b), (32mg, 0.20 mmol) provided, after purification by silica gel chromatography(20:80 hexane:EtOAc), the title compound as a yellow amorphous solid. MS(ESI, pos. ion) m/z: 350 (M+1).

EXAMPLE 81

(2E)-3-[6-(tert-Butyl)(3-pyridyl)]-N-[l-(2-hydroxyethyl)indol-5-yl]prop-2-enamide

(a)(2E)-3-[6-(tert-butyl)(3-pyridyl)]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-5-yl}prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (41mg, 0.20 mmol) and1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indole-5-ylamine, Example73(a), (60 mg, 0.20 mmol) provided the title product. MS (ESI, pos. ion)m/z: 478 (M+1).

(b)(2E)-3-[6-(tert-Butyl)(3-pyridyl)]-N-[1-(2-hydroxyethyl)indol-5-yl]prop-2-enamide.Analogous to the procedure used to prepare Example 72, step (c),(2E)-3-[6-(tert-butyl)(3-pyridyl)]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-5-yl}prop-2-enamide,Example 81(a), (75 mg, 0.16 mmol) and tetrabutylammonium fluoride (0.50mL, 0.50 mmol, 1.0 M in THF, Aldrich) provided, after purification bysilica gel chromatography (20:80 hexane:EtOAc), the title compound as ayellow amorphous solid. MS (ESI, pos. ion) m/z: 364 (M+1).

EXAMPLE 82

(2E)-N-Indol-6-yl-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide

(a) 2-Methyl-6-(trifluoromethyl)pyridine-3-carbaldehyde. Analogous tothe procedure used to prepare Example 43, step (b),2-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (5.0 g, 24 mmol,Oakwood) provided the title product. MS (ESI, pos. ion) m/z: 190 (M+1).

(b) (2E)-3-[2-Methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid.Analogous to the procedure used to prepare Example 40, step (a),2-methyl-6-(trifluoromethyl)pyridine-3-carbaldehyde, Example 82(a), (3.7g, 20 mmol) and triethyl phosphonoacetate (4.5 g, 20 mmol, Aldrich)provided the title product. MS (ESI, pos. ion) m/z: 232 (M+1).

(c)(2E)-N-Indol-6-yl-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid,Example 82(b), (58 mg, 0.25 mmol) and 6-aminoindole (33 mg, 0.25 mmol,Lancaster) provided, after purification by silica gel chromatography(55:45 hexane:EtOAc), the title compound as a yellow solid. MP 223° C.MS (ESI, pos. ion) m/z: 346 (M+1).

EXAMPLE 83

(2E)-N-Indol-5-yl-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid,Example 82(b), (120 mg, 0.50 mmol) and 5-aminoindole (66 mg, 0.50 mmol,Aldrich) provided, after purification by silica gel chromatography(55:45 hexane:EtOAc), the title compound as a yellow solid. MP 231° C.MS (ESI, pos. ion) m/z: 346 (M+1).

EXAMPLE 84

(2E)-N-Benzothiazol-6-yl-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid,Example 82(b), (120 mg, 0.50 mmol) and 6-aminobenzothiazole (75 mg, 0.50mmol, Lancaster) provided, after purification by silica gelchromatography (55:45 hexane:EtOAc), the title compound as a whitesolid. MP 196° C. MS (ESI, pos. ion) m/z: 364 (M+1).

EXAMPLE 85

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[2-methyl-6-(trifluoromethyl)-(3-pyridyl)]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid,Example 82(b), (120 mg, 0.50 mmol) and 1,4-benzodioxan-6-amine (76 mg,0.50 mmol, Aldrich) provided, after purification by silica gelchromatography (55:45 hexane:EtOAc), the title compound as a yellowsolid. MP 186° C. MS (ESI, pos. ion) m/z: 365 (M+1).

EXAMPLE 86

(2E)-3-[4-(tert-butyl)phenyl]-N-[3-(hydroxymethyl)-2-oxo(7-1,3,4-trihydroquinolyl)]prop-2-enamide

(a) (2-Amino-4-nitrophenyl)methan-1-ol. To a solution of4-nitroanthranilic acid (910 mg, 5.0 mmol, Aldrich) in THF (15 mL),magnetically stirred at 0° C., was added borane-tetrahydrofuran complex(15 mL, 15 mmol, 1.0 M in THF, Aldrich) dropwise. The reaction mixturewas heated to reflux overnight. The mixture was then cooled to 0° C. andtreated dropwise with MeOH (5 mL) followed by 1 N NaOH (30 mL). Afterstirring for 30 min at room temperature, the mixture was extracted withEtOAc (2×50 mL). The combined organic phases were washed with satd NaCl(20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (50% EtOAc/hexane) followed byrecrystallization from EtOAc/hexane provided the title product. MS (ESI,pos. ion) m/z: 169 (M+1).

(b) 2-Amino-4-nitrobenzaldehyde. A mixture of2-amino-4-nitrophenyl)methan-1-ol, Example 86(a), (336 mg, 2.0 mmol) andMnO₂ (3.48 g, 40.0 mmol, Aldrich) in CH₂Cl₂/hexane (1:1, 10 mL) wasstirred at room temperature for 1 h. The suspension was filtered andwashed with CH₂Cl₂. The filtrate was concentrated in vacuo to give thecrude product. MS (ESI, pos. ion) m/z: 167 (M+1).

(c) Methyl 7-nitro-2-oxo-1,3,4-trihydroquinoline-3-carboxylate. Amixture of 2-amino-4-nitrobenzaldehyde, Example 86(b), (1.66 g, 10.0mmol), dimethyl malonate (1.37 mL, 12.0 mmol, Aldrich), copper (II)acetate (100 mg, 0.5 mmol, Aldrich) and potassium acetate (99 mg, 1.0mmol, Bayer) in acetic acid (20 mL) was stirred at 110° C. for 48 h.Most of the solvent was removed in vacuo and the resulting precipitatewas collected by filtration, washed with EtOAc and dried in vacuo togive the title product. MS (ESI, pos. ion) m/z: 248 (M+1)

(d) 3-(Hydroxymethyl)-7-nitro-1,3,4-trihydroquinolin-2-one and(7-nitro-3-1,2,3,4-tetrahydroquinolyl)methan-1-ol. To a solution ofmethyl 7-nitro-2-oxo-1,3,4-trihydroquinoline-3-carboxylate, Example86(c), (1.23 g, 5.0 mmol) in THF (50 mL) was added LiBH₄ (12.5 mL, 25.0mmol, 2.0 M in THF, Aldrich). The reaction mixture was stirred at 40° C.for 18 h, then quenched by the careful addition of satd NH₄Cl (20 mL).The mixture was stirred at room temperature for 30 min, then extractedwith EtOAc (2×50 mL). The combined organic phases were washed with satdNaCl (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (50% EtOAc/CH₂Cl₂) provided3-(hydroxymethyl)-7-nitro-1,3,4-trihydroquinolin-2-one [MS (ESI, pos.ion) m/z: 223 (M+1)] and(7-nitro-3-1,2,3,4-tetrahydroquinolyl)methan-1-ol [MS (ESI, pos. ion)m/z: 209 (M+1)].

(e) 7-Amino-3-(hydroxymethyl)-1,3,4-trihydroquinolin-2-one. Analogous tothe procedure used to prepare Example 3, step (a),3-(hydroxymethyl)-7-nitro-1,3,4-trihydroquinolin-2-one, Example 86(d),(66 mg, 0.30 mmol) provided, after purification by silica gelchromatography (10% MeOH/CH₂Cl₂), the title compound. MS (ESI, pos. ion)m/z: 193 (M+1).

(f)(2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(hydroxymethyl)-2-oxo(7-1,3,4-trihydroquinolyl)]prop-2-enamide.Analogous to the procedure used to prepare Example 1,4-tert-butyl-trans-cinnamic acid (67 mg, 0.33 mmol, EMKA-Chemie) and7-amino-3-(hydroxymethyl)-1,3,4-trihydroquinolin-2-one, Example 86(e),(52 mg, 0.27 mmol) provided, after purification by silica gelchromatography (10% MeOH/EtOAc), the title compound as a pale yellowsolid. MP 201-203° C. MS (ESI, pos. ion) m/z: 379 (M+1).

EXAMPLE 87

(2E)-N-[3-(Hydroxymethyl)(7-1,2,3,4-tetrahydroquinolyl)]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide

(a) (7-Amino-3-1,2,3,4-tetrahydroquinolyl)methan-1-ol. Analogous to theprocedure used to prepare Example 3, step (a),(7-nitro-3-1,2,3,4-tetrahydroquinolyl)methan-1-ol, Example 86(d), (140mg, 0.68 mmol) provided, after purification by silica gel chromatography(10% MeOH/CH₂Cl₂), the title compound. MS (ESI, pos. ion) m/z: 179(M+1).

(b)(2E)-N-[3-(Hydroxymethyl)(7-1,2,3,4-tetrahydroquinolyl)]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide.Analogous to the procedure used to prepare Example 1,trans-4-(trifluoromethyl)cinnamic acid (120 mg, 0.55 mmol, Aldrich) and(7-amino-3-1,2,3,4-tetrahydroquinolyl)methan-1-ol, Example 87(a), (98mg, 0.55 mmol) provided, after purification by silica gel chromatography(10% MeOH/EtOAc), the title compound as a pale yellow solid. MP 176-179°C. MS (ESI, pos. ion) m/z: 377 (M+1).

EXAMPLE 88

(2E)-N-[3-(hydroxymethyl)-1-methyl(7-1,2,3,4-tetrahydroquinolyl)]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide

A mixture of(2E)-N-[3-(hydroxymethyl)(7-1,2,3,4-tetrahydroquinolyl)]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide,Example 87, (75 mg, 0.20 mmol), iodomethane (0.014 mL, 0.22 mmol,Aldrich) and NaHCO₃ (84 mg, 1.0 mmol) in DMF (1.0 mL, Aldrich) wasstirred for 4 h at room temperature. Water (5 mL) was added and themixture was extracted with EtOAc (2×20 mL). The combined organic phaseswere washed with water (5 mL), satd NaCl (5 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (60% EtOAc/CH₂Cl₂) provided the title product as a whitesolid. MP 167-169° C. MS (ESI, pos. ion) m/z: 391 (M+1).

EXAMPLE 89

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-5-(1,3-dioxolan-2-yl)pent-2-enamide

Analogous to the procedure used to prepare Example 53(a),(1,3-dioxolan-2-ylethyl)zinc bromide (3.0 mL, 1.5 mmol, 0.5 M THFsolution, Rieke) andN-(2H,3H-benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enamide,Example 55, (0.23 g, 0.50 mmol) provided, after purification by silicagel chromatography (gradient: 30%-35% EtOAc/hexane), the title productas an amorphous white solid. MS (ESI, pos. ion) m/z: 438 (M+1).

EXAMPLE 90

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-4-(3-pyridyl)but-2-enamide

(a). 3-(Tributylstannanylmethyl)pyridine. Analogous to the procedure ofKaiser, E. M. and Petty, J. D. Synthesis 1975, 705-706, to a 50 mLround-bottomed flask equipped with magnetic stirring was added lithiumdiisopropylamide (5.2 mL, 10 mmol, 2.0 M in heptane/THF/ethylbenzene,Aldrich) at 0° C. under nitrogen, followed by hexamethylphosphoramide(1.8 mL, 10 mmol, Aldrich). The mixture was stirred for 15 min, thentreated with a solution of 3-picoline (1.0 mL, 10 mmol, Aldrich) in THF(4 mL) over 5 min. The reaction mixture was stirred for 30 min, then asolution of tributyltin chloride (2.8 mL, 10 mmol, Aldrich) in THF (6mL) was added. The resulting solution was gradually warmed to roomtemperature and concentrated in vacuo. Purification by silica gelchromatography (gradient: 2%-5% EtOAc/hexane) provided the title productas a colorless oil. MS (ESI, pos. ion) m/z: 382 (M+1).

(b)(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-4-(3-pyridyl)but-2-enamide.To a 50 mL round-bottomed flask, equipped with magnetic stirring, wasadded 3-(tributylstannanylmethyl)pyridine, Example 90(a), (0.37 g, 0.97mmol),N-(2H,3H-benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enamide,Example 55, (0.30 g, 0.65 mmol), 1-methyl-2-pyrrolidinone (2.5 mL,Aldrich), and tetrakis(triphenylphosphine)-palladium (0) (75 mg, 0.06mmol, Aldrich). The reaction mixture was stirred at 110° C. overnight,then diluted with EtOAc (100 mL), washed with satd NaHCO₃, water andsatd NaCl. The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography(25%-45% EtOAc/hexane) was followed by reverse phase preparative HPLC(CH₃CN/H₂O with 0.1% TFA). The fractions containing desired product wereneutralized with NaHCO₃. The mixture was extracted with CH₂Cl₂ and theorganic phase concentrated in vacuo to provide the title product as anamorphous white solid. MS (ESI, pos. ion) m/z: 429 (M+1).

EXAMPLE 91

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-4-pyrrolidinylbut-2-enamide

(a). Methyl (2E)-3-[4-(tert-butyl)phenyl]but-2-enoate. To a 100 m]Lround-bottomed flask purged with N₂ was added1-bromo-4-tert-butylbenzene (2.34 g, 11.0 mmol, Aldrich), methylcrotonate (1.08 mL, 10 mmol, Aldrich), N-methyldicyclohexylamine (3.31mL, 15 mmol, Aldrich), palladium acetate (0.045 g, 0.20 mmol, Aldrich),tetraethylammonium chloride (1.66 g, 10.0 mmol, Fluka), andN,N-dimethylacetamide (40 mL, Aldrich). The reaction mixture wasmagnetically stirred at 100° C. overnight, then allowed to cool to 25°C., diluted with Et₂O, and filtered through Celite. The solution waswashed with H₂O (3×), dried over MgSO₄, filtered, and concentrated invacuo. Purification by silica gel chromatography (gradient: 0.5%-3%dichloromethane in hexane) provided the title product as a colorlessoil. MS (ESI, pos. ion) m/z: 233 (M+1).

(b) Methyl (2Z)-3-[4-(tert-butyl)phenyl]-4-pyrrolidinylbut-2-enoate. Asolution of methyl (2E)-3-[4-(tert-butyl)phenyl]but-2-enoate, Example91(a), (0.37 g, 1.6 mmol) in CCl₄ (15 mL), magnetically stirred in a 50mL round-bottomed flask under N₂, was treated with N-bromosuccinimide(0.31 g, 1.75 mmol, Aldrich) and 2,2′-azobisisobutyronitrile (5 mg, 0.03mmol, Aldrich). The reaction mixture was magnetically stirred underreflux overnight, then allowed to cool to 25° C. The solid was filtered.The filtrate was concentrated in vacuo to afford a yellow oil [MS (ESI,pos. ion) m/z: 311, 313 (M+1, M+3)]. To a solution of the yellow oil inTBF (5 mL), was added pyrrolidine (0.16 mL, 1.9 mmol, Aldrich) andN,N-diisopropylethylamine (0.33 mL, 1.9 mmol, Aldrich). The reactionmixture was magnetically stirred at room temperature overnight, thenconcentrated in vacuo. The residue was treated with water and extractedwith dichloromethane (3×). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to afford a yellow oil. Purificationby silica gel chromatography (gradient: 4%-20% EtOAc/hexane) providedthe title product as a pale yellow oil. MS (ESI, pos. ion) m/z: 302(M+1).

(c).N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-4-pyrrolidinylbut-2-enamide.To a 50 mL round-bottomed flask charged with methyl(2Z)-3-[4-(tert-butyl)phenyl]-4-pyrrolidinylbut-2-enoate, Example 91(b),(188 mg, 0.62 mmol) was added THF (2 mL), MeOH (0.2 mL), H₂O (1 mL), andlithium hydroxide monohydrate (54 mg, 1.25 mmol, Aldrich). The reactionmixture was magnetically stirred at room temperature overnight. Theexcess lithium hydroxide was removed by filtration. The mixture waspurified by reverse phase preparative HPLC (CH₃CN/H₂O with 0.1% TFA),concentrated in vacuo, then treated with an excess of HCl in Et₂O.Concentration in vacuo provided a pale yellow solid 0.15 g [MS (ESI,pos. ion) m/z: 288 (M+1)]. Analogous to the procedure used to prepareExample 1, the solid (77 mg) and 1,4-benzodioxan-6-amine (61 mg, 0.40mmol, Aldrich) provided the crude title product. Purification by silicagel chromatography (gradient: 1-5% MeOH in CH₂Cl₂) was followed byreverse phase preparative HPLC (CH₃CN/H₂O with 0.1% TFA). The fractionscontaining desired product were neutralized with NaHCO₃. The mixture wasextracted with CH₂Cl₂ and the organic phase concentrated in vacuo toprovide the title product as a pale yellow oil. MS (ESI, pos. ion) m/z:421 (M+1).

EXAMPLE 92

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enamide

(a). Ethyl(2E)-3-[4-(tert-butyl)phenyl]-5-(1,3-dioxolan-2-yl)pent-2-enoate.Analogous to the procedure used to prepare Example 53(a), starting from(1,3-dioxolan-2-ylethyl)zinc bromide (0.5 M TBIF solution, 40 mL, 20mmol, Rieke) and ethyl(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate, Example 52(b), (3.58g, 10.0 mmol), the title product was obtained as a colorless oil. MS(ESI, pos. ion) m/z: 333 (M+1).

(b). Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-oxohex-2-enoate. To around-bottomed flask was added ethyl(2E)-3-[4-(tert-butyl)phenyl]-5-(1,3-dioxolan-2-yl)pent-2-enoate,Example 92(a), (2.7 g, 8.1 mmol), THF (3 mL), and 5 N HCl (12 mL). Thereaction mixture was initially stirred at room temperature for 24 h,then heated to 40° C. overnight. The pH was adjusted to ˜5-6 by theaddition of NaHCO₃ and the mixture was extracted with EtOAc. Thecombined organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by silica gel chromatography (5%EtOAc/hexane) provided the title product as a white solid. MS (ESI, pos.ion) m/z: 289 (M+1).

(c). Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-hydroxyhex-2-enoate. Tosolution of ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-oxohex-2-enoate,Example 92(b), (1.5 g, 5.3 mmol) in MeOH (18 mL), magnetically stirredat 0° C. in a 100 mL round-bottomed flask, was added sodium borohydride(0.40 g, 11 mmol, Aldrich). The mixture was allowed to gradually warm upto room temperature over 2 h, then quenched with water (20 mL) andextracted with EtOAc (4×). The organic extract was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by silica gelchromatography (15% EtOAc/hexane) provided the title product as acolorless oil in quantitative yield. MS (PSI, pos. ion) m/z: 291 (M+1).

(d). Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-iodohex-2-enoate. To a 100 mLround-bottomed flask charged with ethyl(2E)-3-[4-(tert-butyl)phenyl]-6-hydroxyhex-2-enoate, Example 92(c),(0.80 g, 2.7 mmol) and CH₂Cl₂ (10 mL) at room temperature, was addedtriphenylphosphine (0.87 g, 3.3 mmol, Aldrich), imidazole (0.22 g, 3.3mmol, Aldrich), and 12 (1.2 g, 4.7 mmol, Aldrich). The reaction mixturewas stirred for 2 h, filtered and concentrated in vacuo. Purification bysilica gel chromatography (3% EtOAc/hexane) provided the title productas a white semi-solid in quantitative yield. MS (ESI, pos. ion) m/z: 401(M+1).

(e) Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enoate. To a100 mL round-bottomed flask charged with ethyl(2E)-3-[4-(tert-butyl)phenyl]-6-iodohex-2-enoate, Example 92(d), (1.1 g,2.7 mmol), imidazole (0.20 g, 3.0 mmol, Aldrich), benzyltriethylammoniumchloride (63 mg, 0.30 mmol, Aldrich), and CH₂Cl₂ (15 mL), stirredmagnetically at room temperature, was added potassium hydroxide (50%aqueous solution, 1.5 mL). The reaction mixture was stirred at 50° C.overnight, then diluted with water. The reaction mixture was extractedwith CH₂Cl₂. The organic solution was dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by silica gel chromatography (50%EtOAc/hexane) provided the title product as a pale yellow oil. MS (ESI,pos. ion) m/z: 341 (M+1).

(f) (2E)-3-[4-(tert-Butyl)phenyl]-6-imidazolylhex-2-enoic acid. To a 50mL round-bottomed flask equipped with a reflux condenser was added ethyl(2E)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enoate, Example 92(e),(0.35 g, 1.0 mmol), THF (6 mL) and KOH (50% aqueous solution, 1.5 mL).The reaction mixture was heated and magnetically stirred under refluxovernight, then concentrated in vacuo and acidified with glacial aceticacid to pH ˜4-5. The aqueous mixture was extracted with CH₂Cl₂ and theorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (5%-10% MeOH/CH₂Cl₂) providedthe title product as a white solid. MS (ESI, pos. ion) m/z: 313 (M+1).

(g)(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enoic acid, Example92(f), (76 mg, 0.24 mmol) and 1,4-benzodioxan-6-amine (36 mg, 0.24 mmol,Aldrich) provided, after purification by silica gel chromatography (3%-5% MeOHWCH₂Cl₂), the title product as an amorphous off-white solid. MS(ESI, pos. ion) m/z: 446 (M+1).

EXAMPLE 93

3-(4-tert-Butyl-phenyl)-6-imidazol-1-yl-hex-2-enoic acidbenzothiazol-6-ylamide. Analogous to the procedure used to prepareExample 1, (2E)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enoic acid,Example 92(f), (76 mg, 0.24 mmol) and 6-aminobenzothiazole (36 mg, 0.24mmol, Lancaster) provided, after purification by silica gelchromatography (3% -5% MeOH/CH₂Cl₂), the title compound as a whitesolid. MS (ESI, pos. ion) m/z: 445 (M+1).

EXAMPLE 94

(2E)-N-(2H,3H-benzo[e]1,4-dioxan-6-yl)-3-[2-morpholin-4-yl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide

(a) 2-Morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carboxylic acid. To around-bottomed flask was added 2-chloro-6-trifluoromethylnicotinic acid(2.0 g, 8.9 mmol, Matrix) and morpholine (5.0 g, 57 mmol, Aldrich). Thereaction mixture was magnetically stirred at 25° C. for 48 h, thendiluted with 1 N HCl (100 mL) and extracted with EtOAc (100 mL). Theaqueous phase was saturated with NaCl and extracted again with EtOAc (50mL). The combined EtOAc extracts were washed with 1 N HCl (50 mL), satdNaCl (50 mL), dried over MgSO₄, filtered and concentrated in vacuo toafford the title product as an off-white waxy solid. MS (ESI, pos. ion)m/z: 277 (M+1).

(b) [2-Morpholin-4-yl-6-(trifluoromethyl)-3-pyridyl]methan-1-ol. Asolution of 2-morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carboxylicacid, Example 94(a), (2.1 g, 7.6 mmol) in anhydrous THF (20 mL) wastreated dropwise with lithium aluminum hydride (15 mL, 15 mmol, 1.0 M inTHF, Aldrich) with stirring under N₂ at 25° C. The reaction mixture wasstirred at 25° C. for 1.5 h, then quenched by the dropwise addition of a10% aqueous solution of Rochelle salt (50 mL, potassium sodium tartrate,Aldrich). EtOAc (50 mL) was added and the bi-phasic mixture stirredvigorously for 2 h at 25° C. The mixture was diluted with water (100 mL)and the phases separated. The aqueous phase was extracted with EtOAc(2×75 mL), the organic phases were combined and washed with 1 N NaOH(2×75 mL), satd NaCl (75 mL), dried over MgSO₄, filtered andconcentrated in vacuo to afford the title product as a viscous yellowoil. MS (ESI, pos. ion) m/z: 263 (M+1).

(c) 2-Morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carbaldehyde. Asolution of oxalyl chloride (3.6 mL, 7.2 mmol, 2.0 M in CH₂Cl₂, Aldrich)in anhydrous CH₂Cl₂ (20 mL) was magnetically stirred under N₂, in anoven-dried round-bottomed flask, at −60° C. The solution was treateddropwise with methyl sulfoxide (1.1 mL, 15 mmol, Aldrich) then stirredfor 10 min. A solution of[2-morpholin-4-yl-6-(trifluoromethyl)-3-pyridyl]methan-1-ol, Example94(b), (1.7 g, 6.5 mmol) in anhydrous CH₂Cl₂ (20 mL) was added viacannula, and the reaction mixture stirred at −60° C. for 15 min.Triethylamine (4.5 mL, 32 mmol, Aldrich) was added, the cooling bath wasremoved, and the reaction mixture allowed to warm to 25° C. and stirredat that temperature for 1 h. The mixture was washed with water (30 mL)and the aqueous wash was back-extracted with CH₂Cl₂ (2×20 mL). Thecombined organic phase was washed with water (30 mL), satd NaCl (30 mL),dried over MgSO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (9:1 hexane:EtOAc) provided the title productas a viscous yellow oil. MS (ESI, pos. ion) m/z: 261 (M+1).

(d) (2E)-3-[2-Morpholin-4-yl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoicacid. Analogous to the procedure described for Example 40, step (a),2-morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carbaldehyde, Example94(c), (1.2 g, 4.6 mmol) provided the title product as a yellow solid.MS (ESI, pos. ion) m/z: 303 (M+1).

(e)(2E)-N-(2H,3H-benzo[e]1,4-dioxan-6-yl)-3-[2-morpholin-4-yl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide.(2E)-3-[2-Morpholin-4-yl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoicacid, Example 94(d), (200 mg, 0.66 mmol) was dissolved in anhydrousCH₂Cl₂ (10 mL) and treated with oxalyl chloride (0.36 mL, 0.72 mmol, 2.0M in CH₂Cl₂, Aldrich) and anhydrous DMF (2 uL). The reaction mixture wasstirred at reflux for 30 min, then concentrated in vacuo. The residuewas dissolved in anhydrous CH₂Cl₂ (10 mL), treated with pyridine (0.27mL, 3.5 mmol, Aldrich) and 1,4-benzodioxan-6-amine (120 mg, 0.79 mmol,Aldrich) and stirred at reflux for 15 min. The reaction mixture wasconcentrated in vacuo and the residue dissolved in EtOAc (75 mL). Themixture was washed with 1 N HCl (2×50 mL), 1 N NaOH (50 mL), water (50mL), satd NaCl (50 mL), dried over MgSO₄, filtered and concentrated invacuo. Recrystallization from EtOAc and hexane provided the titleproduct as pale tan crystals. MP 200-201° C. MS (ESI, pos. ion) m/z: 436(M+1).

EXAMPLE 95

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)-2-bromophenyl]prop-2-enamide

(a) 4-(tert-Butyl)-2-bromo-1-(bromomethyl)benzene. According to theprocedure of Kikuchi, D. et al, J. Org. Chem. 1998, 63, 6023-6026, to asolution of sodium bromate (22 g, 145 mmol, Aldrich) in water (75 mL),magnetically stirred in an Erlenmeyer flask at 25° C., was added asolution of 4-t-butyltoluene (5.0 mL, 29 mmol, Aldrich) in acetonitrile(60 mL). The bi-phasic mixture was vigorously stirred while a solutionof sodium bisulfite (15 g, 145 mmol, Baker) in water (150 mL) was addeddropwise, via addition funnel, over 20 min. The reaction mixture wasstirred for 6 h, then extracted with Et₂O (300 mL). The organic phasewas washed with satd aq. Na₂S₂O₃ (2×100 mL), satd NaCl (50 mL), driedover MgSO₄, filtered and concentrated in vacuo to afford of the titleproduct as a pale orange oil.

(b) 4-(tert-Butyl)-2-bromobenzaldehyde. According to the procedure ofMallory, et al, Tetrahedron 2001, 57, 3715-3724, a solution of sodiumethoxide (12 mL, 32 mmol, 21% in EtOH, Aldrich) in absolute EtOH (100mL) was magnetically stirred under N₂ at 25° C. and treated with2-nitropropane (2.9 mL, 32 mmol, Aldrich) followed by4-(tert-butyl)-2-bromo-1-(bromomethyl)benzene, Example 95(a), (9.0 g, 29mmol). The reaction mixture was stirred at 25° C. for 5 h, thenconcentrated in vacuo to an orange solid. The solid was partitionedbetween Et₂O (150 mL) and water (100 mL). The layers were separated andthe organic phase was washed with water (100 mL), 1 N NaOH (2×75 mL),satd NaCl (50 mL), dried over MgSO₄, filtered and concentrated in vacuoto afford the title product as an orange oil.

(c) (2E)-3-[4-(tert-Butyl)-2-bromophenyl]prop-2-enoic acid. Analogous tothe procedure described for Example 40, step (a),4-(tert-butyl)-2-bromobenzaldehyde, Example 95(b), (6.5 g, 27 mmol)provided the title product as a white solid. MS (ESI, pos. ion) m/z:283, 285 (M, M+2).

(d)(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)-2-bromophenyl]prop-2-enamide.Analogous to the procedure described for Example 94, step (e),(2E)-3-[4-(tert-butyl)-2-bromophenyl]prop-2-enoic acid, Example 95(c),(3.0 g, 11 mmol) and 1,4-benzodioxan-6-amine (1.9 g, 13 mmol, Aldrich)provided, after recrystallization from CH₂Cl₂ and hexane, the titleproduct as off-white crystals. MP 206-210° C. MS (ESI, pos. ion) m/z:416, 418 (M, M+2).

EXAMPLE 96

Ethyl2-[(1E)-2-(N-(2H,3H-benzo[e]1,4-dioxan-6-yl)carbamoyl)vinyl]-5-(tert-butyl)benzoate

According to the procedure of Ma, et al, J. Org. Chem. 1999, 64,120-125, a solution of(2E)-N-(2H,3H-benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)-2-bromophenyl]prop-2-enamide,Example 95, (200 mg, 0.48 mmol) in anhydrous EtOH (5 mL) and methylsulfoxide (5 mL) was treated with triethylamine (0.67 mL, 0.48 mmol,Aldrich) and 1,3-bis(diphenylphosphino)propane (50 mg, 0.12 mmol,Aldrich). The mixture was purged with a stream of carbon monoxide, thentreated with palladium acetate (22 mg, 0.10 mmol, Aldrich), and stirredunder a balloon of carbon monoxide in a 70° C. oil bath for 3 h. Thereaction mixture was allowed to cool to 25° C. and partitioned betweenEtOAc (50 mL) and water (20 mL). The organic phase was washed with water(10 mL), satd NaCl (10 mL), dried over MgSO₄, filtered and concentratedin vacuo. Purification by silica gel chromatography (step gradient, 4:1then 3:1, hexane:EtOAc), followed by recrystallization from EtOAc andhexane, provided the title product as white crystals. MP 155° C. MS(ESI, pos. ion) m/z: 410 (M+1).

EXAMPLE 97

(2E)-3-[2-Bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide

(a) 2-Bromo-4-(trifluoromethyl)benzoic acid. To a solution of2-bromo-1-methyl-4-trifluoromethylbenzene (7.6 g, 32 mmol, ABCR) inpyridine (75 mL) was added tetraethylammonium permanganate (24 g, 96mmol, prepared according to the procedure of Sala, et al. J. Chem. Soc.,Chem. Comm. 1978, 253). The reaction mixture was warmed to 70° C. andstirred at that temperature for 30 h. The reaction mixture was allowedto cool to 25° C. and poured into an ice bath containing cond HCl (150mL) and NaHSO₃ (150 g). The mixture turned to a clear aqueous solutionand was extracted with EtOAc (4×200 mL). The combined extracts werewashed with satd NaCl (200 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to provide the title product as a white solid. MS(ESI, neg. ion) m/z: 267 (M−1).

(b) [2-Bromo-4-(trifluoromethyl)phenyl]methan-1-ol. Analogous to theprocedure used to prepare Example 46, step (a),2-bromo-4-(trifluoromethyl)benzoic acid, Example 97(a), (5.4 g, 20 mmol)provided, after purificaton by silica gel chromatography (gradient:0-10% EtOAc in hexane), the title product as a white solid. MS (ESI,neg. ion) m/z: 313 (M+acetate).

(c) 2-Bromo-4-(trifluoromethyl)benzaldehyde. Analogous to the procedureused to prepare Example 46, step (b),[2-bromo-4-(trifluoromethyl)phenyl]methan-1-ol, Example 97(b), (4.6 g,18 mmol) provided, after purificaton by silica gel chromatography(gradient: 0-4% EtOAc in hexane), the title product as a colorless oil.

(d) Methyl (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoate.Analogous to the procedure used to prepare Example 46, step (c),2-bromo-4-(trifluoromethyl)benzaldehyde, Example 97(c), (2.3 g, 8.9mmol) and carbomethoxymethylene triphenylphosphorane (4.2 g, 12.5 mmol,Aldrich) provided, after purificaton by silica gel chromatography(gradient: 0-3% EtOAc in hexane), the title product as a white solid.

(e) (2E)-3-[2-Bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid.Analogous to the procedure used to prepare Example 46, step (d), methyl(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoate, Example 97(d),(2.25 g, 8.9 mmol) provided the title product.

(f)(2E)-3-[2-Bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example97(e), (140 mg, 0.48 mmol) and 5-aminoindole (75 mg, 0.57 mmol, Aldrich)provided, after purification by silica gel chromatography (gradient:0-25% EtOAc in hexane), the title compound as a yellow solid. MP205-207° C. MS (ESI, pos. ion) m/z: 409 (M+1).

EXAMPLE 98

(2E)-N-Benzothiazol-6-yl-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example97(e), (140 mg, 0.47 mmol) and 6-aminobenzothiazole (86 mg, 0.57 mmol,Lancaster) provided, after purification by silica gel chromatography(gradient: 0-30% EtOAc in hexane), the title product as an off-whitesolid. MP 214-215° C. MS (ESI, pos. ion) m/z: 427 (M+1).

EXAMPLE 99

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[2-bromo-4-(trifluoromethyl)-phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example97(e), (140 mg, 0.47 mmol) and 1,4-benzodioxan-6-amine (86 mg, 0.57mmol, Aldrich) provided, after purification by silica gel chromatography(gradient: 0-18% EtOAc in hexane), the title product as an off-whitesolid. MP 212-213° C. MS (ESI, pos. ion) m/z: 428 (M+1).

EXAMPLE 100

(2E)-N-indol-5-yl-3-[2-(6-methoxy(3-pyridyl))-4-(trifluoromethyl)phenyl]-prop-2-enamide

A mixture of(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide,Example 97, (100 mg, 0.24 mmol), 2-methoxy-5-pyridineboronic acid (60mg, 0.39 mmol, Digital Specialty Chemicals),tris(dibenzylideneacetone)-dipalladium(0) (22 mg, 0.024 mmol, Aldrich)and triphenylphosphine (26 mg, 0.098 mmol, Aldrich) in toluene (1.2 mL),2.0M aqueous Na₂CO₃ (0.4 mL) and ethanol (0.4 mL) was stirred at 120° C.overnight. The reaction mixture was filtered through a pad of Celite anddiluted with water (50 mL). The aqueous phase was extracted with EtOAc(3×60 mL). The combined extracts were washed with satd NaCl (100 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (gradient: 0-20% EtOAc in hexane) provided thetitle product as a yellow solid. MP 219-221° C. MS (ESI, pos. ion) m/z:438 (M+1).

EXAMPLE 101

(2E)-N-Indol-5-yl-3-[2-(4-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 100,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide,Example 97, (120 mg, 0.29 mmol) and pyridine-4-boronic acid (72 mg, 0.59mmol, Frontier Scientific) provided, after purification by silica gelchromatography (gradient: 0-60% EtOAc in hexane), the title product as ayellow solid. MP 229-234° C. MS (ESI, pos. ion) m/z: 408 (M+1).

EXAMPLE 102

(2E)-N-Indol-5-yl-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 100,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide,Example 97, (120 mg, 0.29 mmol) and pyridine-3-boronic acid (58 mg, 0.47mmol, Frontier Scientific) provided, after purification by silica gelchromatography (gradient: 0-20% EtOAc in hexane), the title product as ayellow solid. MP 196-197° C. MS (ESI, pos. ion) m/z: 408 (M+1).

EXAMPLE 103

tert-Butyl4-{2-[(1E)-2-(N-indol-5-ylcarbamoyl)vinyl]-5-(trifluoromethyl)phenyl}-1,2,5,6-tetrahydropyridinecarboxylate

Analogous to the procedure used to prepare Example 100,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide,Example 97, (100 mg, 0.24 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (130 mg, 0.42 mmol, prepared according to theprocedures of Wustrow, D. J. et al, Synthesis 1991, 993 and Ishiyama, T.et al, J. Org. Chem. 1995, 60, 7508) provided, after purification bysilica gel chromatography (gradient: 0-35% EtOAc in hexane), the titleproduct as an amorphous yellow solid. MS (ESI, pos. ion) m/z: 512 (M+1).

EXAMPLE 104

(2E)-N-Indol-5-yl-3-[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 100,(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide,Example 97, (100 mg, 0.24 mmol) and 2-tributylstannylthiazole (155 mg,0.42 mmol, Frontier Scientific) provided, after purification by silicagel chromatography (gradient: 0-35% EtOAc in hexane), the title productas an orange solid. MP 203-204° C. MS (ESI, pos. ion) m/z: 414 (M+1).

EXAMPLE 105

(2E)-N-Indol-5-yl-3-[2-(3-pyridylmethyl)-4-(trifluoromethyl)phenyl]prop-2-enamide

A mixture of(2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide,Example 97, (110 mg, 0.27 mmol), 3-(tributylstannanylmethyl)pyridine,Example 90(a), (160 mg, 0.43 mmol),tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.027 mmol, Aldrich)and triphenylphosphine (28 mg, 0.11 mmol, Aldrich) in1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 100° C. overnight. Thereaction mixture was filtered through a pad of Celite and diluted withwater (50 mL). The aqueous phase was extracted with EtOAc (3×60 mL). Thecombined organic extracts were washed with satd NaCl (100 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by silicagel chromatography (gradient: 0-70% EtOAc in hexane) provided the titlecompound as an orange solid. MP 202-203° C. MS (ESI, neg. ion) m/z: 420(M−1).

EXAMPLE 106

(2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl]-N-(7-quinolyl)prop-2-enamide

(a) Methyl(2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoate. A mixtureof methyl (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoate,Example 97(d), (585 mg, 1.89 mmol), pyridine-3-boronic acid (950 mg, 2.8mmol, Frontier Scientific), tris(dibenzylideneacetone)dipalladium (0)(170 mg, 0.19 mmol, Aldrich) and triphenylphosphine (200 mg, 0.76 mmol,Aldrich) in toluene (5 mL), 1.0 M aqueous Na₂CO₃ (2 mL) and ethanol (2mL) was stirred at 80° C. under N₂ overnight. The reaction mixture wasfiltered through a pad of Celite and diluted with water (60 mL). Theaqueous phase was extracted with EtOAc (3×60 mL). The combined organicextracts were washed with satd NaCl (100 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (gradient: 0-35% EtOAc in hexane) provided the titleproduct as a yellow solid. MS (ESI, pos. ion) m/z: 308 (M+1).

(b) (2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid. Amixture of methyl(2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoate, Example106(a), (540 mg, 1.8 mmol) and LiOH monohydrate (370 mg, 8.8 mmol) inwet ethanol (5 mL) was stirred at room temperature overnight. Thereaction mixture was neutralized with aqueous HCl (2.0 M, 4.4 mL, 8.8mmol) and concentrated under reduced pressure. The material was driedunder vacuum at 60° C. for 4 h to provide 955 mg of the crude material,which contained LiCl as a byproduct. MS (ESI, pos. ion) m/z: 294 (M+1).

(c)(2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl]-N-(7-quinolyl)prop-2-enamide.Analogous to the procedure used to prepare Example 1,(2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid,Example 106(b), (185 mg) and 7-aminoquinoline (64 mg, 0.44 mmol, Specs)provided, after purification by silica gel chromatography (gradient:0-75% EtOAc in hexane), the title compound as an amorphous off-whitesolid. MS (ESI, pos. ion) m/z: 420 (M+1).

EXAMPLE 107

(2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl]-N-(3-quinolyl)prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid,Example 106(b), (185 mg) and 3-aminoquinoline (64 mg, 0.44 mmol,Aldrich) provided, after purification by silica gel chromatography(gradient: 0-45% EtOAc in hexane), the title compound as a white solid.MP 196-199° C. MS (ESI, pos. ion) m/z: 420 (M+1).

EXAMPLE 108

(2E)-N-Indol-6-yl-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enamide

Analogous to the procedure used to prepare Example 1,(2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid,Example 106(b), (185 mg) and 6-aminoindole (59 mg, 0.44 mmol, Aldrich)provided, after purification by silica gel chromatography (gradient:0-50% EtOAc in hexane), the title compound as an amorphous orange solid.MS (ESI, pos. ion) m/z: 408 (M+1).

EXAMPLE 109

N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]propanamide

(a)(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-prop-2-enamide.A solution of 4-t-butyl-trans-cinnamic acid (500 mg, 2.45 mmol,EMKA-Chemie) in anhydrous CH₂Cl₂ (10 mL) was-magnetically stirred andtreated with oxalyl chloride (0.22 mL, 2.5 mmol, Aldrich) and DMF (0.005mL). The reaction mixture was stirred at reflux for 30 min, thenconcentrated in vacuo. The residue was dissolved in acetone (1 mL) andadded to a mixture of 1,4-benzodioxan-6-amine (370 mg, 2.45 mmol,Aldrich) and K₂CO₃ (500 mg) in acetone (2 mL) and water (4 mL), stirredat 0° C. The reaction mixture was vigorously stirred at 0° C. for 30min, then diluted with ice water (50 mL). The resulting solidprecipitate was collected by filtration and dissolved in CH₂Cl₂ (20 mL)and Et₂O (150 mL). The organic solution was washed with 1 N HCl (3×75mL), satd NaCl (50 mL), dried over MgSO₄, filtered and concentrated toafford the title product as an off-white foam. MS (ESI, pos. ion) m/z:338 (M+1).

(b)N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]propanamide.(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide,Example 109(a), (200 mg, 0.59 mmol) was dissolved in EtOH (25 mL),purged with N₂, treated with 10% Pd on carbon (50 mg, Aldrich) thenpurged with H₂ and the suspension stirred at 25° C., under 1 atm H₂, for16 hr. The suspension was purged with N₂, filtered through a pad ofCelite, and concentrated in vacuo to a white foam. Purification bysilica gel chromatography (45:45: 10 hexane:CH₂Cl₂:EtOAc) provided thetitle product as a clear glass. MS (ESI, pos. ion) m/z: 340 (M+1).

(a) 4-[4-(tert-Butyl)phenyl]pyridine

To 4-bromopyridine hydrochloride (Aldrich) (8.9 g, 46 mmol) andtetrakis(triphenylphosphine)palladium(0) (Aldrich) (1.6 g, 1.4 mmol) wasadded 1,2-dimethoxyethane (250 mL) with stirring under nitrogen. After20 min, a solution of Na₂CO₃ (9.7 g in 70 mL of water) and4-tert-butylbenzeneboronic acid (9.8 g, 55 mmol) were added sequentiallyto the mixture. The reaction was stirred at reflux overnight. Thereaction mixture was concentrated in vacuo to approximately ⅓ itsoriginal volume, and the mixture was extracted with EtOAc (2×100 mL).The combined EtOAc layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. Purification by silica gel chromatography (1:5EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos.ion) m/z: 212 (M+1).

(b) 4-[4-(tert-Butyl)phenyl]pyridine 1-oxide

To the mixture of 4-[4-(tert-butyl)phenyl]pyridine (8.7 g, 41 mmol) andmethyltrioxorhenium (VII) (Aldrich) (170 mg, 0.7 mmol) in a 100-mLround-bottomed flask was added CH₂Cl₂ (18 mL). The mixture was thentreated with 12 mL of hydrogen peroxide (Aldrich) dropwise. The reactionwas stirred at room temperature under nitrogen overnight. Methylenechloride and brine were then added, and the aqueous layer was extractedwith CH₂Cl₂ (40 mL). The organic layer was dried over Na₂SO₄,concentrated in vacuo to give the title compound as an off-white solid.MS (ESI, pos. ion) m/z: 228 (M+1).

(c) 4-[4-(tert-Butyl)phenyl]-2-bromopyridine

To triphenylphosphine (Aldrich) (2.4 g, 9.1 mmol) dissolved in 10 mL ofCH₂Cl₂ in a 50-mL round-bottomed flask was added bromine (Aldrich) (0.43mL, 8.5 mmol). After stirring at 0° C. for 10 min,4-[4-(tert-butyl)phenyl]pyridine 1-oxide (1.5 g, 6.5 mmol) was addeddropwise, followed by Et₃N (1.2 mL, 8.5 mmol). The reaction mixture wasstirred at ₀° C. for 1 h and then at room temperature overnight.Methylene chloride and brine were added, and the aqueous layer wasextracted with CH₂Cl₂. The organic layer was collected and dried overNa₂SO₄, filtered and concentrated in vacuo. Following purification bysilica gel chromatography (10:1 hexane:EtOAc), the title compound wasobtained as a pale yellow oil. MS (ESI, pos. ion) m/z: 293 (M+1).

(d)2H,3H-Benzo[e]1,4-dioxan-6-yl{4-[4-(tert-butyl)phenyl](2-pyridyl)}amine

To an oven-dried 50-mL round-bottomed flask were added4-[4-(tert-butyl)phenyl]-2-bromopyridine (180 mg, 0.63 mmol) and1,4-benzodioxan-6-amine (Aldrich) (191 mg, 1.3 mmol), followed byanhydrous toluene (60 mL) and DMF (6 mL). Nitrogen was bubbled throughthe above solution via a needle for 1 h. Then palladium acetate(Aldrich) (21 mg, 0.01 mmol) and BINAP (Aldrich) (59 mg, 0.01 mmol) wereintroduced to the reaction followed by sodium tert-butoxide (Aldrich)(170 mg, 1.8 mmol). The reaction mixture was heated in a 90 C oil bathovernight. After cooling to room temperature, the reaction mixture wasdissolved in ether, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. Following purification by silica gelchromatography (3:1 hexane:EtOAc), the title compound was obtained as apale tan solid. MS (ESI, pos. ion) m/z: 361 (M+1) MP: 162-163° C. TABLEA The following compounds were prepared according to General Schemes Iand II: MS (ESI, Melting Example Structure pos. ion) m/z Point ° C. 111

303 (M + 1) 157 112

333 (M + 1) amorphous 113

347 (M + 1) 156 114

331 (M + 1) 133 115

393 (M + 1) amorphous 116

342 (M + 1) 106 117

360 (M + 1) 154 118

354 (M + 1) 214 119

372 (M + 1) 203 120

366 (M + 1) 206 121

373 (M + 1) 114 122

383, 385 (M, M + 2) 124 123

354 (M + 1) ?

EXAMPLE 124

(a) N2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-pyridine-2,4-diamine

In a 5-mL vial was added 4-amino-2-chloropyridine (Aldrich ChemicalCompany) (1.1 g, 8.7 mmol), 1,4-benzodioxane-6-amine (Aldrich ChemicalCompany) (5.3 g, 35 mmol) and copper (I) iodide (Aldrich ChemicalCompany) (0.17 g, 0.87 mmol). The content was sonicated at roomtemperature for 5 min and then heated in the Smith Microwave Synthesizerat 200° C. for 10 min. The residue was purified by flash chromatography(95:5 dichloromethane:2N NH₃ in MeOH) to give the title compound as adark solid. MS (ESI, pos. ion) m/z: 244 (M+1).

(b) (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine

Isopentyl nitrile (Aldrich Chemical Company) (3.9 mL, 29 mmol) was addedto a mixture ofN2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-2,4-diamine (Example2(a), 2.4 g, 9.8 mmol), potassium iodide (Aldrich Chemical Company) (1.6g, 9.8 mmol), iodine (Aldrich Chemical Company) (1.2 g, 4.9 mmol) andcopper (I) iodide (Aldrich Chemical Company) (1.9 g, 9.8 mmol) in1,2-dimethoxyethane (60 mL). The reaction mixture was heated at 60-65°C. for 1 hr. After cooling to room temperature, the insoluble materialswere removed by filtration and the filtrate was diluted with EtOAc,washed with 25% aqueous NH₄OH, 5% aqueous sodium bisulfite and thenbrine. The organic layer was separated, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified on a Biotage 40 M column(2.5:1 hexane:EtOAc) to give the title compound as an off-white solid.MS (ESI, pos. ion) m/z: 355 (M+1).

(c)(4-Benzo[1,3]dioxol-5-yl-pyridin-2-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine

In a 5 mL vial were added(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example2(b), 75 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0)(Aldrich Chemical Company) (12 mg, 0.011 mmol) and 1,2-dimethoxyethane(2 mL). After stirring under nitrogen for 10 min, aqueous Na₂CO₃ (22 mgin 0.5 mL of water) and 3,4-(methylenedioxy)phenylboronic acid (AldrichChemical Company) (42 mg, 0.25 mmol) were introduced. The reaction washeated in the Smith Microwave Synthesizer at 150° C. for 10 min. Theresidue was partitioned between EtOAc and brine. The aqueous layer wasextracted with EtOAc and the combined EtOAc layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. Purification on a Biotage40 S column (4:1 hexane:EtOAc) gave the title compound as a light-yellowsolid. MS (ESI, pos. ion) m/z: 349 (M+1). Mp: 116.0-118.0° C.

EXAMPLE 125

(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[4-(4-dimethylamino-phenyl)-pyridin-2-yl]-amine

Following the same procedure described for Example 401(c), the mixtureof (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine(Example 401(b), 75 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich Chemical Company) (12mg, 0.011 mmol), N,N-dimethylaminobenzeneboronic acid (Aldrich ChemicalCompany) (41 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, afterheated in the Microwave Smith Synthesizer at 150° C. for 10 min andpurification on a Biotage 40S column (1.5:1 hexane:EtOAc), the titlecompound as a tan solid. MS (ESI, pos. ion) m/z: 348 (M+1). Mp:154.0-155.5° C.

EXAMPLE 126

(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[4-(4-fluoro-phenyl)-pyridin-2-yl]-amine

Following the same procedure described for Example 401 (c), the mixtureof (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine(Example 401 (b), 75 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich Chemical Company) (12mg, 0.011 mmol), 4-fluorobenzeneboronic acid (Avocado Chemical Company)(35 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated inthe Microwave Smith Synthesizer at 150° C. for 10 min and purificationon a Biotage 40S column (3:1 hexane:EtOAc), the title compound as anoff-white solid. MS (ESI, pos. ion) m/z: 323 (M+1). Mp: 134.5-135.0° C.

EXAMPLE 127

(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[4-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-amine

Following the same procedure described for Example 401(c), the mixtureof (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine(Example 401 (b), 75 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich Chemical Company) (12mg, 0.011 mmol), 3-(trifluoromethyl)phenylboronic acid (Aldrich ChemicalCompany) (47 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, afterheated in the Microwave Smith Synthesizer at 150° C. for 10 min andpurification on a Biotage 40S column (4:1 hexane:EtOAc), the titlecompound as a light-yellow solid. MS (ESI, pos. ion) m/z: 373 (M+1). Mp:138.9-140.5° C.

EXAMPLE 128

(4-Benzo[b]thiophen-2-yl-pyridin-2-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine

Following the same procedure described for Example 401(c), the mixtureof (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine(Example 401(b), 75 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich Chemical Company) (12mg, 0.011 mmol), benzothiophene-2-boronic acid (Frontier Scientific,Inc.) (45 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, afterheated in the Microwave Smith Synthesizer at 150° C. for 10 min andpurification on a Biotage 40S column (4:1 hexane:EtOAc), the titlecompound as a light-yellow solid. MS (ESI, pos. ion) m/z: 361 (M+1). Mp:154.0-154.1° C.

EXAMPLE 129

1-{4-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-pyridin-4-yl]-phenyl}-ethanone

Following the similar procedure described for Example 401(c), themixture of(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example401 (b), 0.73 g, 2.1 mmol), tetrakis(triphenylphosphine)palladium(0)(Aldrich Chemical Company) (0.12 g, 0.11 mmol), 4-actylphenylboronicacid (Aldrich Chemical Company) (0.41 g, 2.5 mmol) and1,2-dimethoxyethane (20 mL) gave, after heated at 90° C. overnight andpurification on a Biotage 40M column (3:1 hexane:EtOAc), the titlecompound as a light-orange solid. MS (ESI, pos. ion) m/z: 347 (M+1). Mp:178.0-180.5° C.

EXAMPLE 130

1-14-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-pyridin-4-yl]-phenyl]-ethanol

To the suspension of1-{4-[2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-pyridin-4-yl]-phenyl}-ethanone(Example 7, 0.19 g, 0.55 mmol) in 2 mL of MeOH was added a solution ofmethylamine in MeOH (Aldrich Chemical Company) (2N, 0.55 mL, 1.1 mmol).The reaction was stirred at room temperature under nitrogen overnight.NaBH₄ (Aldrich Chemical Company) (25 mg, 0.66 mmol) was then added tothe reaction and it was stirred for another 5 hrs. The solvent wasevaporated the residue was purified on a Biotage 40M column (97:3dichloromethane:2N NH₃ in MeOH) to give the title compound as anoff-white foam. MS (ESI, pos. ion) m/z: 349 (M+1). Mp: 55.9-61.5° C.

EXAMPLE 131

[4-(3,5-Bis-trifluoromethyl-phenyl)-pyridin-2-yl]-(2,3-dihydro-benzo[1,4]-dioxin-6-yl)-amine

Following the same procedure described for Example 401 (c), the mixtureof (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine(Example 401 (b), 75 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich Chemical Company) (12mg, 0.011 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (AldrichChemical Company) (64 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL)gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10min and purification on a Biotage 40S column (4:1 hexane:EtOAc), thetitle compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 441(M+1). Mp: 130.0-131.5° C.

EXAMPLE 132

(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[4-(4-trifluoromethoxy-phenyl)-pyridin-2-yl]-amine

Following the same procedure described for Example 401 (c), the mixtureof (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine(Example 401 (b), 75 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich Chemical Company) (12mg, 0.011 mmol), 4-(trifluoromethoxy)phenylboronic acid (LancasterSynthesis Ltd.) (51 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave,after heated in the Microwave Smith Synthesizer at 150° C. for 10 minand purification on a Biotage 40S column (4:1 hexane:EtOAc), the titlecompound as an orange glass. MS (ESI, pos. ion) m/z: 389 (M+1).

EXAMPLE 133

(a) 4-(4-Trifluoromethyl-phenyl)-pyridine

In a 250-mL, round-bottomed flask were added 4-bromopyridinehydrochloride (Aldrich) (4.7 g, 24 mmol),tetrakis(triphenylphosphine)palladium(0) (Aldrich) (1.4 g, 1.2 mmol) and1,2-dimethoxyethane (120 mL). After stirring under nitrogen for 10 min,a solution of Na₂CO₃ (5.2 g in 30 mL of water) and4-trifluoromethylbenzeneboronic acid (5.1 g, 27 mmol) were addedsequentially to the mixture. The reaction was stirred in a 90° C. oilbath overnight. The 1,2-dimethoxyethane was evaporated in vacuo, andEtOAc was added to the residue. The aqueous layer was separated andextracted with EtOAc (2×50 mL). The combined EtOAc extracts were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. Purification bysilica gel flash chromatography using 1:5 EtOAc/hexanes as eluent gavethe title compound as a light-tan solid. MS (ESI, pos. ion) m/z: 224(M+1).

(b) 4-(4-Trifluoromethyl-phenyl)-pyridine 1-oxide

To a mixture of 4-(4-trifluoromethyl-phenyl)-pyridine (5.0 g, 22 mmol)and methyltrioxorhenium (VII) (Aldrich) (110 mg, 0.45 mmol) in a 100-mL,round-bottomed flask was added CH₂Cl₂ (10 mL). Hydrogen peroxide (5 mL,Aldrich) was added drop-wise, and the reaction was stirred at roomtemperature under N₂ for 48 h. The mixture was partitioned betweenCH₂Cl₂ and brine, and the aqueous layer was extracted with CH₂Cl₂ (40mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound as an off-white solid.MS (ESI, pos. ion) m/z: 240 (M+1).

(c) 2-Chloro-4-(4-trifluoromethyl-phenyl)-pyridine

To 4-(4-trifluoromethyl-phenyl)-pyridine 1-oxide (2.4 g, 10 mmol) wasadded phosphorous oxychloride (12 mL) at room temperature. The reactionmixture was heated at reflux for 5 h. POCl₃ was removed under reducedpressure, and the residue was partitioned between EtOAc and aqueousammonium hydroxide. The aqueous layer was extracted with EtOAc and thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified by chromatographyon a Biotage 40 M column (8:1 hexanes:EtOAc) to give the title compoundas a white solid. MS (ESI, pos. ion) m/z: 258.5 (M+1).

(d) Quinolin-3-yl-[4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-amine

To an oven-dried 50 mL round-bottomed flask were added2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (138 mg, 0.54 mmol) and3-aminoquinoline (Aldrich Chemical Company) (93 mg, 0.64 mmol), followedby anhydrous toluene (45 mL). Nitrogen was bubbled through the abovesolution via a needle for 1 h. Then palladium acetate (Aldrich ChemicalCompany) (18 mg, 0.08 mmol) and BINAP (Aldrich Chemical Company) (50 mg,0.08 mmol) were added to the reaction in one portion, followed by sodiumtert-butoxide (Aldrich Chemical Company) (145 mg, 1.5 mmol). Thereaction mixture was heated at 90° C. overnight. After cooling to roomtemperature, the reaction mixture was taken up to ether, and washed withbrine. The aqueous layer was extracted with ether (2×) and the combinedether layer was dried over Na₂SO₄ and concentrated. The residue waspurified on a Biotage 40 S column (2.5:1 hexane:EtOAc) to give the titlecompound as an off-white solid. MS (ESI, pos. ion) m/z: 366 (M+1). Mp:207.4-207.5° C.

EXAMPLE 134

7-[4-(4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinoline

To an oven-dried, 50-mL, round-bottomed flask were added7-hydroxyquinoline (Aldrich) (87 mg, 0.6 mmol) and DMF (1 mL). Thesolution was place under nitrogen, and NaH (24 mg, 0.6 mmol) was addedin one portion. After stirring for 10 min,2-chloro-4-(4-trifluoromethylphenyl) pyridine (Example 410 (c), 129 mg,0.5 mmol) was added. The reaction mixture was heated in a 155° C. oilbath for 72 h. After cooling to room temperature, the reaction mixturewas partitioned between EtOAc and brine. The aqueous layer was extractedwith EtOAc and the combined organic layers were dried over Na₂SO₄,concentrated in vacuo. The crude material was purified on a Biotage 40 Scolumn (3:1 hexanes:EtOAc) to give the title compound as an off-whitesolid. MS (ESI, pos. ion) m/z: 367 (M+1). Mp: 156.5-158.5° C.

EXAMPLE 135

2-(3-Methoxy-phenoxy)-4-(4-trifluoromethyl-phenyl)-pyridine

This material was prepared according to the method described in Example2 (d) using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410(c), 129 mg, 0.5 mmol), 3-methoxyphenol (66 uL, 0.6 mmol), and sodiumhydride (24 mg, 0.6 mmol) in DMF (1 mL). Purification on a Biotage 40Scolumn (8:1 hexanes:EtOAc), provided the title compound as a whitesolid. MS (ESI, pos. ion) m/z: 346 (M+1). Mp: 77.5-79.6° C.

EXAMPLE 136

8-[4-(4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinolin-2-ylamine

A mixture of 2-azido-quinolin-8-ol (0.28 g, 1.5 mmol),2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.26 g,1 mmol), and sodium hydride (64 mg, 1.6 mmol) in DMF (2 mL) was heatedin a 180° C. oil bath for 48 h. The reaction mixture was thentransferred to a 5-mL tube, and irradiated in the Microwave SmithSynthesizer at 250° C. for 10 min. EtOAc and brine were added, and theaqueous layer was extracted with EtOAc. Combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The compound waspurified on a Biotage 40S column (98:2 dichloromethane:MeOH) followed byrecrystallization from EtOAc/hexanes to give the title compound as alight-yellow shiny crystal. MS (ESI, pos. ion) m/z: 382 (M+1). Mp:196.5-199.5° C. Anal. Calcd for C₂₁H₁₄F₃N₃O: C, 66.14; H, 3.70; N,11.02. Found: C, 66.18; H, 3.69; N, 11.08.

EXAMPLE 137

8-[4-(4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinoline

This material was prepared according to the method described in Example413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410(c), 0.16 g, 0.6 mmol), 8-hydroxyquinoline (0.1 g, 0.7 mmol), sodiumhydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) inDMF (3 mL). Purification on a Biotage 40S column (3:1 hexanes:EtOAc),provided the title compound as a white solid. MS (ESI, pos. ion) m/z:367 (M+1). Anal. Calcd for C₂₁H₁₃F₃N₂O: C, 68.85; H, 3.58; N, 7.65.Found: C, 68.88; H, 3.59; N, 7.51.

EXAMPLE 138

2-Methyl-5-[4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazole

This material was prepared according to the method described in Example413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410(c), 0.16 g, 0.6 mmol), 2-methyl-5-benzothiazolol (0.12 g, 0.7 mmol),sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06mmol) in DMF (3 mL). Purification on a Biotage 40S column (3:1hexanes:EtOAc), provided the title compound as a white solid. MS (ESI,pos. ion) m/z: 367 (M+1). Mp: 160.5-163.5° C. Anal. Calcd forC₂₀H₁₃F₃N₂OS. 0.25 H₂O: C, 61.45; H, 3.48; N, 7.17; S, 8.20. Found: C,61.45; H, 3.39; N, 7.17; S, 8.31. TABLE B The following compounds wereprepared according to General Schemes III.a, III.b and III.c: MS (ESI,Melting Example Structure pos. ion) m/z Point ° C. 139

388 (M + 1) 246.3-247.5 140

428 (M − 1) 430 (M + 1)

ADDITIONAL EXAMPLES

Following the procedures described above, or with slight modificationsthereof, and following procedures familiar to one of ordinary skill inthe art, the following examples were prepared from commerciallyavailable reagents: Example Melting Mass Spec. number Structure Point (°C.) (ESI) m/z 142

244 343 (M + 1) 143

231 352, 354 (M, M + 2) 144

159 311 (M + 1) 145

>300  361 (M + 1) 146

59-61 310 (M + 1) 147

174-175 310 (M + 1) 148

 97-102 340 (M + 1) 149

148-152 337 (M + 1) 150

233-237 453 (M + 1) 151

oil 296 (M + 1) 152

106-108 281 (M + 1) 153

98-102 295 (M + 1) 154

171-173 323 (M + 1) 155

257 320 (M + 1) 156

187-190 359 (M + 1) 157

203 339 (M + 1) 158

244-248 416 (M + 1) 159

204 325 (M + 1) 160

191 341 (M + 1) 161

thin film 319 (M + 1) 162

173 326 (M + 1) 163

152 406 (M + 1) 164

193 370 (M + 1) 165

249 365 (M + 1) 166

193 331 (M + 1) 167

149 310 (M + 1) 168

173 310 (M + 1) 169

218 296 (M + 1) 170

195 322 (M + 1) 171

223 323 (M + 1) 172

168 310 (M + 1) 173

205 348 (M + 1) 174

161 338 (M + 1) 175

212 334 (M + 1) 176

263 323 (M + 1) 177

239 331 (M + 1) 178

167 347 (M + 1) 179

172 330 (M + 1) 180

154 336 (M + 1) 181

281 337 (M + 1) 182

154 347 (M + 1) 183

105 328 (M + 1) 184

165 329 (M + 1) 185

270 331 (M + 1) 186

 68 331 (M + 1) 187

261 320 (M + 1) 188

277 321 (M + 1) 189

194 319 (M + 1) 190

101 319 (M + 1) 200

258 336 (M + 1) 201

178 352 (M + 1) 202

196 395 (M + 1) 203

222 333 (M + 1) 204

218 391 (M + 1) 205

296-298 348 (M + 1) 206

189 515 (M) 207

116-119 470 (M + 1) 208

186 352 (M + 1) 209

162-163 302 (M + 1) 210

231-232 333 (M + 1) 211

42-48 300 (M + 1) 212

229-230 300 (M + 1) 213

200-202 368 (M + 1) 214

120 338 (M + 1) 215

119 310 (M + 1) 216

 69 352 (M + 1) 217

amorphous glass 351 (M + 1) 218

84-90 338 (M + 1) 219

64-71 428 (M + 1) 220

100-104 415 (M + 1) 221

91-93 428 (M + 1) 222

205-206 415 (M + 1) 223

78-80 444 (M + 1) 224

89-93 444 (M + 1) 225

148-150 444 (M + 1) 226

92-94 445 (M + 1) 227

177-180 396 (M + 1) 228

138-141 428 (M + 1) 229

155 448 (M + 1) 230

168 432 (M + 1) 231

121-124 426 (M + 1) 232

403 (M + 1) 233

 87 513 (M + 1) 234

415 (M + 1) 235

amorphous 427 (M + 1) 236

 56 499 (M + 1) 237

497 (M + 1) 238

207-208 395 (M + 1) 239

188-189 423 (M + 1) 240

198-199 380 (M + 1) 241

201-203 394 (M + 1) 242

171-173 381 (M + 1) 243

118-120 422 (M + 1) 244

101-103 408 (M + 1) 245

126-128 408 (M + 1) 246

185-186 394 (M + 1) 247

182-184 423 (M + 1) 248

194-196 381 (M + 1) 249

206-208 394 (M + 1) 250

200-201 427 (M + 1) 251

199-200 379 (M + 1) 252

236-237 441 (M + 1) 253

169 356 (M + 1) 254

256-258 331 (M + 1) 255

264-266 394 (M + 1) 256

102-103 365 (M + 1) 257

137-138 391 (M + 1) 258

198-200 391 (M + 1) 259

171-173 402 (M + 1) 260

158-160 409 (M + 1) 261

168-170 365 (M + 1) 262

179-180 395 (M + 1) 263

117-119 411 (M + 1) 264

187-189 388 (M + 1) 265

154-157 402 (M + 1) 266

160-161 395 (M + 1) 267

152-153 422 (M + 1) 268

186-188 364 (M + 1) 269

134-135 409 (M + 1) 270

182-185 381 (M + 1) 271

171-173 395 (M + 1) 272

101-105 369 (M + 1) 273

176-178 411 (M + 1) 274

196-199 392 (M + 1) 275

146-148 382 (M + 1) 276

231 363 (M + 1) 277

161-162 367 (M + 1) 278

108-110 425 (M + 1) 279

186-187 409 (M + 1) 280

160-162 381 (M + 1) 281

181 363 (M + 1) 282

amorphous 353 (M + 1) 283

(oil) 366 (M) 284

348 (M + 1) 285

324 (M + 1) 286

330 (M + 1) 287

382 (M + 1) 288

294 (M + 1) 289

314 (M + 1) 290

294 (M + 1) 291

308 (M + 1) 292

314 (M + 1) 293

294 (M + 1) 294

367 (M + 1) 295

246-247 341 (M) 296

328 (M + 1) 297

233-235 341 (M) 298

365 (M + 1) 299

362 (M + 1) 300

376 (M) 301

372 (M + 1) 302

186-187 391 (M + 1) 303

224-226 414 (M + 1) 304

231-232 331 (M + 1) 305

219-220 349 (M + 1) 306

231-232 383 (M + 1) 307

203-204 365 (M + 1) 308

117-179 365 (M + 1) 309

226-227 384 (M + 1) 310

Amorphous 308 (M + 1) 311

150 360 (M) 312

211 427 (M + 1) 313

 78 433 (M + 1) 314

286 350 (M + 1) 315

Amorphous 434 (M + 1) 316

226 415 (M + 1) 317

219 530 (M + 1) 318

Amorphous 320 (M + 1) 319

Amorphous 415 (M + 1) 320

211 349 (M + 1) 321

Amorphous 375 (M + 1) 322

Amorphous 341 (M + 1) 323

Amorphous 427 (M + 1) 324

225 360 (M + 1) 325

Amorphous 338 (M + 1) 326

275 320 (M + 1) 327

282 332 (M + 1) 328

209 332 (M + 1) 329

Amorphous 430 (M + 1) 330

197 443 (M + 1) 331

Amorphous 332 (M + 1) 332

Amorphous 448 (M) 333

202 353 (M + 1) 334

229 431 (M + 1) 335

 97 449 (M + 1) 336

121 309 (M) 337

Amorphous 444 (M + 1) 338

Amorphous 462 (M + 1) 339

Amorphous 463 (M + 1) 340

163 366 (M + 1) 341

237-240 427 (M + 1) 342

276-278 463 (M + 1) 343

amorphous 423 (M + 1) 344

202-204 476 (M + 1) 345

214-218 451 (M + 1) 346

amorphous 447 (M + 1) 347

201-205 423 (M + 1) 348

263-269 449 (M + 1) 349

273-275 451 (M + 1) 350

348 (M + 1) 351

295 (M + 1) 352

amorphous 417 (M + 1) 353

308 (M + 1) 354

328 (M + 1) 355

amorphous 435 (M + 1) 356

319 (M + 1) 357

323 (M + 1) 358

323 (M + 1) 359

334 (M + 1) 360

320 (M + 1) 361

324 (M + 1) 362

294 (M + 1) 363

298 (M + 1) 364

385 (M + 1) 365

359 (M + 1) 366

328 (M + 1) 367

325 (M + 1) 368

315 (M + 1) 369

374 (M + 1) 370

305 (M + 1) 371

387 (M + 1) 372

281 (M + 1) 373

358 (M + 1) 374

310 (M + 1) 375

331 (M + 1) 376

282 (M + 1) 377

315 (M + 1) 378

360 (M + 1) 379

344 (M + 1) 380

amorphous 449 (M + 1) 381

amorphous 401 (M + 1) 382

350 (M + 1) 383

351 (M + 1) 384

345 (M + 1) 385

344 (M + 1) 386

339 (M + 1) 387

247-248 327 (M + 1) 388

179-180 312 (M + 1) 389

179-182 360, 362 (M, M + 2) 390

182-183 282 (M + 1) 391

187-188 316 (M + 1) 392

195-196 300 (M + 1) 393

201-202 350 (M + 1) 394

214-216 325 (M + 1) 395

150 360 (M + 1) 396

184-189 350 (M + 1) 397

173-175 296 (M + 1) 398

160-165 318 (M + 1) 399

200 350 (M + 1) 400

203-207 332 (M + 1) 401

155-158 326 (M + 1) 402

181-182 318 (M + 1) 403

196 408 (M + 1) 404

185-186 332 (M + 1) 405

(oil) 322 (M + 1) 406

188 340 (M + 1) 407

176 350 (M + 1) 408

(oil) 326 (M + 1) 409

129 366 (M + 1) 410

202 396 (M + 1) 411

191 362 (M + 1) 412

165 324 (M + 1)

TABLE The following compounds were prepared according to General SchemesI, II or III: Example MS (ESI, Melting number Structure pos. ion) m/zPoint ° C. 413

303 (M + 1) 157 414

333 (M + 1) amorphous 415

347 (M + 1) 156 416

321 (M + 1) 133 417

393 (M + 1) amorphous 418

342 (M + 1) 106 419

360 (M + 1) 154 420

354 (M + 1) 214 421

372 (M + 1) 203 422

366 (M + 1) 206 423

373 (M + 1) 114 424

383, 385 (M, M + 2) 124

ADDITIONAL EXAMPLES

Following the procedures described above, and applying the procedure inExample 109 to the cinnamides exemplified, or with slight modificationsthereof, and following procedures familiar to one of ordinary skill inthe art, the following examples may be prepared from commerciallyavailable reagents:

The following examples may also be made using the above generic schemesand synthetic examples:

Capsaicin-Induced Ca²⁺ Influx in Primary Dorsal Root Ganglion Neurons

Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected fromtimed-pregnant, terminally anesthetized Sprague-Dawley rats (CharlesRiver, Wilmington, Mass.) and collected in ice-cold L-15 media (LifeTechnologies, Grand Island, N.Y.) containing 5% heat inactivated horseserum (Life Technologies). The DRG were then dissociated into singlecell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoidinhibitor, 1 mg/ml ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/ml ovomucoidinhibitor, 10 mg/ml ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88-μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/ml(Sigma) and mouse laminin 1 μg/ml (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F12, 1:1,penicillin (100 U/ml), and streptomycin (100 μg/ml), and nerve growthfactor (10 ng/ml), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity. Forcontrolling the growth of non-neuronal cells, 5-fluoro-2′-deoxyuridine(75 μM) and uridine (180 μM) were included in the medium. Activation ofVR1 was achieved in these cellular assays using either a capsaicinstimulus (ranging from 0.01-10 μM) or by an acid stimulus (addition of30 mM Hepes/Mes buffered at pH 4.1). Compounds were also tested in anassay format to evaluate their agonist properties at VR1. The activationof VR1 is followed as a function of cellular uptake of radioactivecalcium (⁴⁵Ca²⁺:Amersham CES3-2 mCi).

Capsaicin Antagonist Assay: E-19 DRG cells at 3 days in culture areincubated with serial concentrations of VR1 antagonists, in HBSS (Hanksbuffered saline solution supplemented with BSA 0.1 mg/ml and 1 mM Hepesat pH 7.4) for 15 min, room temperature. Cells are then challenged witha VR1 agonist, capsaicin (500 nM), in activation buffer containing 0.1mg/ml BSA, 15 mM Hepes, pH 7.4, and 10 μCi/ml ⁴⁵Ca²⁺ (Amersham CES3-2mCi) in Ham's F12 for 2 min at room temperature.

Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cellsat room temperature for 2 minutes prior to addition of ⁴⁵Ca²⁺ in 30 mMHepes/Mes buffer (Final Assay pH 5) and then left for an additional 2minutes prior to compound washout. Final concentration of ⁴⁵Ca²⁺(Amersham CES3-2 mCi) is 10 μCi/mL.

Agonist Assay: Compounds are incubated with E-19 DRG cells at roomtemperature for 2 minutes in the presence of 45Ca²⁺ prior to compoundwashout. Final 45Ca²⁺ (Amersham CES3-2 mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates are washed using an ELX405plate washer (Bio-Tek Instruments Inc.) immediately after functionalassay. Wash 3× with PBS, 0.1 mg/mL BSA. Aspirate between washes. Readplates using a MicroBeta Jet (Wallac Inc.). Compound activity is thencalculated using appropriate computational algorithms.

⁴⁵Calcium²⁺ Assay Protocol

Compounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells couldbe cultured in a Growth Medium, routinely passaged at 70% confluencyusing trypsin and plated in an assay plate 24 hours prior to compoundevaluation.

Possible Growth Medium:

-   -   DMEM, high glucose (Gibco 11965-084).    -   10% Dialyzed serum (Hyclone SH30079.03).    -   1× Non-Essential Amino Acids (Gibco 11140-050).    -   1× Glutamine-Pen-Strep (Gibco 10378-016).    -   Geneticin, 450 μg/mL (Gibco 10131-035).

Compounds could be diluted in 100% DMSO and tested for activity overseveral log units of concentration [40 μM-2 pM]. Compounds may befurther diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior toevaluation. Final DMSO concentration in assay would be 0.5-1%. Eachassay plate could be controlled with a buffer only and a knownantagonist compound (either capsazepine or one of the described VR1antagonists).

Activation of VR1 could be achieved in these cellular assays usingeither a capsaicin stimulus (ranging from 0.1-1 μM) or by an acidstimulus (addition of 30 mM Hepes/Mes buffered at pH 4.1). Compoundscould also be tested in an assay format to evaluate their agonistproperties at VR1.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells(expressing either human or rat VR1) at room temperature for 2 minutesprior to addition of ⁴⁵Ca²⁺ and Capsaicin and then left for anadditional 2 minutes prior to compound washout. Capsaicin (200 nM) canbe added in HAM's F12, 0.1 mg/mL BSA, 15 mM Hepes at pH 7.4. Final45Ca²⁺ (Amersham CES3-2 mCi) added could be 10μCi/mL.

Acid Antagonist Assay: Compounds can be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition of⁴⁵Ca²⁺ in 30 mM Hepes/Mes buffer (Final Assay pH 5) and then left for anadditional 2 minutes prior to compound washout. Final ⁴⁵Ca²⁺ (AmershamCES3-2 mCi) added could be 10 μCi/mL.

Agonist Assay: Compounds can be incubated with cells (expressing eitherhuman or rat VR1) for 2 minutes in the presence of ⁴⁵Ca²⁺ prior tocompound washout. Final ⁴⁵Ca²⁺ (Amersham CES3-2 mCi) added could be 10μCi/mL.

Compound Washout and Analysis: Assay plates would be washed using anELX405 plate washer (Bio-Tek Instruments Inc.) immediately after thefunctional assay. One could wash 3× with PBS, 0.1 mg/mL BSA, aspiratingbetween washes. Plates could then be read using a MicroBeta Jet (WallacInc.) and compound activity calculated using appropriate computationalalgorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6,406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0. 1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch.

Such dosage forms may also comprise, as in normal practice, additionalsubstances other than inert diluents, e.g., lubricating agents such asmagnesium stearate. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents. Tablets and pills canadditionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one that is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, a-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

wherein: R¹ is a naphthyl, the naphthyl is substituted by 0, 1, 2 or 3substituents independently selected from R⁵, R⁶ and R⁷; R is H, hydroxy,halo, C₁₋₆alkyl substituted by 0, 1 or 2 substituents selected from R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷; R⁴is

R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is optionallyvicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the carbon atoms of the heterocycleand bridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl; or R⁴is 10-membered bicyclic ring comprising fused 6-membered rings,containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbonatoms, with at least one of the 6-membered rings being aromatic, whereinthe carbon atoms are substituted by H, halo, OR^(a), NR^(a)R^(a),C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbon atoms may beadditionally substituted by ═O; except that when R¹ is 4-chlorophenyl,3-bromophenyl, 3-nitrophenyl, 2-nitro-3-chlorophenyl,3,4-methylenedioxyphenyl, 3-methylthiophenyl or 2,3,4-methoxyphenyl,then R⁴ is not phenyl substituted by 1 or 2 substituents selected fromhalo and C₁₋₄alkyl; and R¹ and R⁴ are not both 3,4-methylenedioxyphenyl;and when R¹ is 4-trifluoromethylphenyl, then R⁴is not pyridinyl,2-methyl-4-aminoquinolinyl or 3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl;R⁵ is independently, at each instance, H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkyNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)C₁₋₆alkylOR^(a); or R⁵ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S; R⁶ is independently, at each instance, H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a); or R⁵ and R⁶ together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the bridge are substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₆alkyl, (═O), —OC₁₋₆alkyl, —NR^(a)C₁₋₆alkyl,—C₁₋₆alkylOR^(a) and C₁₋₆alkylNR^(a)R^(a), and the available N atoms ofthe bridge are substituted by R^(a), —C₁₋₆alkylOR^(a) orC₁₋₆alkylNR^(a)R^(a); R⁷ is independently, at each instance, H,C₁₋₉alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a) or—NR^(a)—C₁₋₆alkylOR^(a); R¹⁰ is independently, at each instance, H,C₁₋₉alkyl, —C₁₋₃alkylOR^(a), C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; R¹¹ isindependently, at each instance, H, C₁₋₉alkyl, -C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylR^(c),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; or R¹⁰and R¹¹ together are a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the each of the carbon atoms in thebridge is substituted by H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl,—NR^(a)R^(a), —C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); wherein if R¹⁰, R¹², R¹³ and R¹⁴ are all H, then R¹¹is not —O—C₁₋₆alkylNR^(a)R^(a) or —O—C₁₋₆alkylOR^(a); R¹² isindependently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; or R¹¹ and R¹² together are a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the each ofthe carbon atoms in the bridge is substituted by H, ═O, —OR^(a),—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a), —C₁₋₆alkylNR^(a)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl, —NR^(a)C(═O)C₁₋₆alkyl,—C₁₋₃alkylOC(═O)C₁₋₆alkyl or —C₁₋₃alkylNR^(a)—C(═O)C₁₋₆alkyl, and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(a),—C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c); or R¹⁰and R¹¹ together are -L³-NR^(a)—, respectively, or -L⁴O—, respectively;or R¹¹ and R¹² are —NR^(a)-L³-, -L³-NR^(a)—, —O-L⁴- or -L⁴-O—; or R¹² is—NR^(a)R^(b); or R⁴ is 10-membered bicyclic ring comprising fused6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainderbeing carbon atoms, with at least one of the 6-membered rings beingaromatic, wherein the carbon atoms are substituted by H, halo, OR^(a),NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and saturated carbon atoms maybe additionally substituted by ═O; or R⁴ is a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selectedfrom O, N and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the heterocycle and bridge are substituted by 1, 2 or 3substituents independently selected from C₂₋₉alkyl, C₁₋₄haloalkyl, halo,nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl,—O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)—C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl; R¹³is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR_(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; R¹⁴ is independently, at each instance, H,C₁₋₉alkyl, —C₁₋₃alkylOR^(a), C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; R^(a)is independently, at each instance, H, phenyl, benzyl or C₁₋₆alkyl;R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a); R^(c) isphenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(c) is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the carbon atoms of the heterocycle aresubstituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fusedphenyl ring is substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); L³ is a 2- or 3-atom,saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and0, 1 or 2 atoms independently selected from O, N and S, wherein the eachof the carbon atoms in the bridge is substituted by H, ═O, —OR^(a),—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a), —C₁₋₆alkyNR^(a)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl, —NR^(a)C(═O)C₁₋₆alkyl,—C₁₋₃alkylOC(═O)C₁₋₆alkyl or —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and anynitrogen atoms in the bridge are substituted by H, —C₁₋₆alkylOR^(a),—C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c); L⁴ is a2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3carbon atoms and 0 or 1 atoms independently selected from O, N and S,wherein at least one of the carbon atoms in the bridge is substituted by═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OC₁₋₆alkyl, —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)C₁₋₆alkyl, —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); X is O, S or NR^(a); Y is NH or O; and n isindependently, at each instance, 0, 1 or
 2. 2. A compound according toclaim 1, wherein: R¹ is a naphthyl, the naphthyl is substituted by 0, 1,2 or 3 substituents independently selected from R⁵, R⁶ and R⁷; R² is H,hydroxy, halo, C₁₋₆alkyl substituted by 0, 1 or 2 substituents selectedfrom R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷; and R³ is H or C₁₋₄alkyl. 3.A compound according to claim 2, wherein R² is

or a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,wherein no more than 2 of the ring members are O or S, wherein theheterocycle is optionally fused with a phenyl ring, and the heterocycleor fused phenyl ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵, R⁶ and R⁷.
 4. A compound according toclaim 3, wherein R² is


5. A compound according to claim 3, wherein R² is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵,R⁶ and R⁷.
 6. A compound according to claim 2, wherein: R⁴is

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O^(R) ^(a); and Y² is—NR^(a)— or —O—.
 7. A compound according to claim 2, wherein: R⁴is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0 or 1 atoms independently selected from O, N andS, wherein the each of the carbon atoms in the bridge is substituted byH, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(R) ^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl,C₁₋₆alkyl-O—R^(a); and Y² is —NR^(b)— or —O—.
 8. A compound according toclaim 2, wherein: R⁴is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl,C₁₋₆alkyl-O—R^(a); and Y² is —NR^(b) or —O—.
 9. A compound according toclaim 2, wherein: R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, Nand S, wherein the each of the carbon atoms in the bridge is substitutedby H, ═O, —OR^(a), —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —NR^(a)R^(a),—C₁₋₆alkylNR^(a)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a), —OC(═O)C₁₋₆alkyl,—NR^(a)C(═O)C₁₋₆alkyl, —C₁₋₃alkylOC(═O)C₁₋₆alkyl or—C₁₋₃alkylNR^(a)C(′O)C₁₋₆alkyl, and any nitrogen atoms in the bridge aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl,C₁₋₆alkyl-O—R^(a); and Y² is —NR^(a)— or —O—.
 10. A compound accordingto claim 2, wherein: R⁴is

R^(b) is H, C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, C₁₋₆alkyl-O—R^(a); and Y² is—NR^(a)— or —O—.
 11. A compound according to claim 2, wherein: R⁴ is10-membered bicyclic ring comprising fused 6-membered rings, containing0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with atleast one of the 6-membered rings being aromatic, wherein the carbonatoms are substituted by H, halo, OR^(a), NR^(a)R^(a), C₁₋₆alkyl andC₁₋₃haloalkyl; and saturated carbon atoms may be additionallysubstituted by ═O.
 12. A compound according to claim 2, wherein: R⁴is

R¹⁰ is independently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; R¹¹ is independently, at each instance, H,C₁₋₉alkyl, —C₁₋₃alkylOR^(a), C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylR^(c), —O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a),—N^(a)R^(a), —NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl;C₁₋₆alkylNR^(a)R^(a); R¹² is independently, at each instance, H,C₁₋₉alkyl, —C₁₋₃alkylOR^(a), C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; R¹³ isindependently, at each instance, H, C₁₋₉alkyl, —C₁₋₃alkylOR^(a),C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a), —O—C₁₋₆alkylOR^(a),—O—C₁₋₆alkylC(═O)OR^(a), NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)—C₁₋₆alkylNR^(a)R^(a), —NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; and R¹⁴ is independently, at each instance, H,C₁₋₉alkyl, —C₁₋₃alkylOR^(a), C₁₋₄haloalkyl, halo, nitro, cyano, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —O—C₁₋₄haloalkyl, —O—C₁₋₆alkylNR^(a)R^(a),—O—C₁₋₆alkylOR^(a), —O—C₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)—C₁₋₄haloalkyl, —NR^(a)—C₁₋₆alkylNR^(a)R^(a),—NR^(a)—C₁₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)—C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl;wherein one of R¹⁰ and R¹² is not H.
 13. A compound according to claim2, wherein R⁴ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄haloalkyl, —OR^(a) and—NR^(a)R^(a).
 14. A compound according to claim 1, or apharmaceutically-acceptable salt thereof, wherein the compounds isselected from:


15. A method of treating acute, inflammatory and neuropathic pain,dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders, comprising the step ofadministering a compound according to claim
 1. 16. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.